Artykuły w czasopismach na temat „CYP3A4”
Kliknij ten link, aby zobaczyć inne rodzaje publikacji na ten temat: CYP3A4.
Utwórz poprawne odniesienie w stylach APA, MLA, Chicago, Harvard i wielu innych
Sprawdź 50 najlepszych artykułów w czasopismach naukowych na temat „CYP3A4”.
Przycisk „Dodaj do bibliografii” jest dostępny obok każdej pracy w bibliografii. Użyj go – a my automatycznie utworzymy odniesienie bibliograficzne do wybranej pracy w stylu cytowania, którego potrzebujesz: APA, MLA, Harvard, Chicago, Vancouver itp.
Możesz również pobrać pełny tekst publikacji naukowej w formacie „.pdf” i przeczytać adnotację do pracy online, jeśli odpowiednie parametry są dostępne w metadanych.
Przeglądaj artykuły w czasopismach z różnych dziedzin i twórz odpowiednie bibliografie.
1
Sun, Jie-Yu, Ze-Jun Xu, Fang Sun, Hui-Lei Guo, Xuan-Sheng Ding, Feng Chen i Jing Xu. "Individualized Tacrolimus Therapy for Pediatric Nephrotic Syndrome: Considerations for Ontogeny and Pharmacogenetics of CYP3A". Current Pharmaceutical Design 24, nr 24 (8.11.2018): 2765–73. http://dx.doi.org/10.2174/1381612824666180829101836.
Pełny tekst źródłaStreszczenie:
Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It’s important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.
2
Niwa, Toshiro, Kanae Narita, Ayaka Okamoto, Norie Murayama i Hiroshi Yamazaki. "Comparison of Steroid Hormone Hydroxylations by and Docking to Human Cytochromes P450 3A4 and 3A5". Journal of Pharmacy & Pharmaceutical Sciences 22 (24.07.2019): 332–39. http://dx.doi.org/10.18433/jpps30558.
Pełny tekst źródłaStreszczenie:
Purpose: Hydroxylation activity at the 6β-position of steroid hormones (testosterone, progesterone, and cortisol) by human cytochromes P450 (P450 or CYP) 3A4 and CYP3A5 and their molecular docking energy values were compared to understand the catalytic properties of the major forms of human CYP3A, namely, CYP3A4 and CYP3A5. Methods: Testosterone, progesterone, and cortisol 6β-hydroxylation activities of recombinant CYP3A4 and CYP3A5 were determined by liquid chromatography. Docking simulations of these substrates to the heme moiety of reported crystal structures of CYP3A4 (Protein Data Bank code ITQN) and CYP3A5 (6MJM) were conducted. Results: Michaelis constants (Km) for CYP3A5-mediated 6β-hydroxylation of testosterone and progesterone were approximately twice those for CYP3A4, whereas the value for cortisol 6β-hydroxylation mediated by CYP3A5 was similar to the value for that by CYP3A4. Maximal velocities (Vmax) of the three steroid hormones 6β-hydroxylation catalyzed by CYP3A5 were 30%-63% of those by CYP3A4. Thus, Vmax/ Km values of these hormones for CYP3A5 resulted in 22%-31% of those for CYP3A4. The differences in the docking energies between CYP3A4 and CYP3A5 for steroid hormones were slightly correlated to the logarithm of CYP3A5/CYP3A4 ratios for Km values (substrate affinity). Conclusions: The Vmax, rather than Km values, for CYP3A5-mediated 6β-hydroxylation of three steroid hormones were different from those for CYP3A4. Molecular docking simulations could partially explain the differences in the accessibility of substrates to the heme moiety of human CYP3A molecules, resulting in the enzymatic affinity of CYP3A4 and CYP3A5.
3
Kamdem, Landry K., Frank Streit, Ulrich M. Zanger, Jürgen Brockmöller, Michael Oellerich, Victor W. Armstrong i Leszek Wojnowski. "Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus". Clinical Chemistry 51, nr 8 (1.08.2005): 1374–81. http://dx.doi.org/10.1373/clinchem.2005.050047.
Pełny tekst źródłaStreszczenie:
Abstract Background: Tacrolimus is metabolized predominantly to 13-O-demethyltacrolimus in the liver and intestine by cytochrome P450 3A (CYP3A). Patients with high concentrations of CYP3A5, a CYP3A isoenzyme polymorphically produced in these organs, require higher doses of tacrolimus, but the exact mechanism of this association is unknown. Methods: cDNA-expressed CYP3A enzymes and a bank of human liver microsomes with known CYP3A4 and CYP3A5 content were used to investigate the contribution of CYP3A5 to the metabolism of tacrolimus to 13-O-demethyltacrolimus as quantified by liquid chromatography–tandem mass spectrometry. Results: Demethylation of tacrolimus to 13-O-demethyltacrolimus was the predominant clearance reaction. Calculated Km and Vmax values for CYP3A4, CYP3A5, and CYP3A7 cDNA-expressed microsomes were 1.5 μmol/L and 0.72 pmol · (pmol P450)−1 · min−1, 1.4 μmol/L and 1.1 pmol · (pmol P450)−1 · min−1, and 6 μmol/L and 0.084 pmol · (pmol P450)−1 · min−1, respectively. Recombinant CYP3A5 metabolized tacrolimus with a catalytic efficiency (Vmax/Km) that was 64% higher than that of CYP3A4. The contribution of CYP3A5 to 13-O-demethylation of tacrolimus in human liver microsomes varied from 1.5% to 40% (median, 18.8%). There was an inverse association between the contribution of CYP3A5 to 13-O-demethylation and the amount of 3A4 protein (r = 0.90; P <0.0001). Mean 13-O-demethylation clearances in CYP3A5 high and low expressers, estimated by the parallel-tube liver model, were 8.6 and 3.57 mL · min−1 · (kg of body weight)−1, respectively (P = 0.0088). Conclusions: CYP3A5 affects metabolism of tacrolimus, thus explaining the association between CYP3A5 genotype and tacrolimus dosage. The importance of CYP3A5 status for tacrolimus clearance is also dependent on the concomitant CYP3A4 activity.
4
Maruf, AA, MU Ahmed, M. A. K. Azad, M. Ahmed i A. Hasnat. "CYP3A Genotypes in Bangladeshi Tuberculosis Patients". Bangladesh Medical Research Council Bulletin 38, nr 1 (22.04.2012): 1–5. http://dx.doi.org/10.3329/bmrcb.v38i1.6978.
Pełny tekst źródłaStreszczenie:
The purpose of this study is to investigate the genotype and allelic frequencies of CYP3A in Bangladeshi Tuberculosis (TB) patients which may help for individualized drug dosing and improved therapeutics. Genotyping was done using the extracted genomic DNA from 90 TB patients followed by amplification of target alleles by PCR. Amplified alleles were then digested by restriction enzymes followed by gel electrophoresis & sequencing to identify the targeted alleles namely CYP3A4*1B, CYP3A4*2, CYP3A4*4, CY3A4*5, CYP3A4*6, CYP3A4*10, CYP3A4*18, and CYP3A5*3. In TB patients, no samples were positive for CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*10, and CYP3A4*18 alleles. One sample was found to be heterozygous for CYP3A4*1B (1.11%). The wild homozygous (CYP3A5*1/*1) genotype frequency was 7.78%, the heterozygous (CYP3A5*1/*3) frequency was 42.22% and the homozygous mutant (CYP3A5*3/*3) frequency was 50% in Bangladeshi TB patients. The absence of the common polymorphic gene suggests that there will be no impact of CYP3A drug metabolizing enzymes on antituberculosis drugs.DOI: http://dx.doi.org/10.3329/bmrcb.v38i1.6978Bangladesh Med Res Counc Bull 2012; 38: 1-5
5
Klees, Theresa Mariero, Pamela Sheffels, Kenneth E. Thummel i Evan D. Kharasch. "Pharmacogenetic Determinants of Human Liver Microsomal Alfentanil Metabolism and the Role of Cytochrome P450 3A5". Anesthesiology 102, nr 3 (1.03.2005): 550–56. http://dx.doi.org/10.1097/00000542-200503000-00012.
Pełny tekst źródłaStreszczenie:
Background There is considerable unexplained interindividual variability in the clearance of alfentanil. Alfentanil undergoes extensive metabolism by cytochrome P4503A4 (CYP3A4). CYP3A5 is structurally similar to CYP3A4 and metabolizes most CYP3A4 substrates but is polymorphically expressed. Livers with the CYP3A5*1 allele contain higher amounts of the native CYP3A5 protein than livers homozygous for the mutant CYP3A5*3 allele. This investigation tested the hypothesis that alfentanil is a substrate for CYP3A5 and that CYP3A5 pharmacogenetic variability influences human liver alfentanil metabolism. Methods Alfentanil metabolism to noralfentanil and N-phenylpropionamide was determined in microsomes from two groups of human livers, characterized for CYP3A4 and CYP3A5 protein content: low CYP3A5 (2.0-5.2% of total CYP3A, n = 10) and high CYP3A5 (46-76% of total CYP3A, n = 10). Mean CYP3A4 content was the same in both groups. The effects of the CYP3A inhibitors troleandomycin and ketoconazole, the latter being more potent toward CYP3A4, on alfentanil metabolism were also determined. Results In the low versus high CYP3A5 livers, respectively, noralfentanil formation was 77 +/- 31 versus 255 +/- 170 pmol . min . mg, N-phenylpropionamide formation was 8.0 +/- 3.1 versus 20.5 +/- 14.0 pmol . min . mg, and the metabolite ratio was 9.5 +/- 0.4 versus 12.7 +/- 1.4 (P < 0.05 for all). There was a poor correlation between alfentanil metabolism and CYP3A4 content but an excellent correlation when CYP3A5 (i.e., total CYP3A content) was considered (r = 0.81, P < 0.0001). Troleandomycin inhibited alfentanil metabolism similarly in the low and high CYP3A5 livers; ketoconazole inhibition was less in the high CYP3A5 livers. Conclusion In microsomes from human livers expressing the CYP3A5*1 allele and containing higher amounts of CYP3A5 protein, compared with those with the CYP3A5*3 allele and little CYP3A5, there was greater alfentanil metabolism, metabolite ratios more closely resembled those for expressed CYP3A5, and inhibitors with differing CYP3A4 and CYP3A5 selectivities had effects resembling those for expressed CYP3A5. Therefore, alfentanil is metabolized by human liver microsomal CYP3A5 in addition to CYP3A4, and pharmacogenetic variability in CYP3A5 expression significantly influences human liver alfentanil metabolism in vitro. Further investigation is warranted to assess whether the CYP3A5 polymorphism is a factor in the interindividual variability of alfentanil metabolism and clearance in vivo.
6
Leskelä, S., E. Honrado, C. Montero-Conde, I. Landa, A. Cascón, R. Letón, P. Talavera i in. "Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer". Endocrine-Related Cancer 14, nr 3 (wrzesień 2007): 645–54. http://dx.doi.org/10.1677/erc-07-0078.
Pełny tekst źródłaStreszczenie:
Testosterone is essential for the growth and function of the luminal prostate cells, but it is also critical for the development of prostate cancer, which in the majority of the cases derives from luminal cells. Cytochrome P450 3A (CYP3A) enzymes hydroxylate testosterone and dehydroepiandrosterone to less active metabolites, which might be the basis for the association between CYP3A polymorphisms and prostate cancer. However, it is unknown whether the CYP3A enzymes are expressed at relevant levels in the prostate and which polymorphisms could affect this tissue-specific CYP3A activity. Thus, we measured CYP3A4, CYP3A5, CYP3A7, and CYP3A43 mRNA in 14 benign prostatic hyperplasias and ten matched non-tumoral/tumoral prostate samples. We found that CYP3A5 mRNA in non-tumoral prostate tissue was 10% of the average amount of liver samples, whereas the expression of the other CYP3A genes was much lower. Similarly to liver, CYP3A5*3 polymorphism decreased CYP3A5 mRNA content 13-fold. CYP3A5 protein was detected in non-tumoral prostate microsomes by western blot, and immunohistochemistry (IHC) localized CYP3A5 exclusively in the basolateral prostate cells. In contrast to the normal tissue, IHC and RT-PCR showed that tumoral tissue lacked CYP3A5 expression. In conclusion, prostate basolateral cells express high levels of CYP3A5 which dramatically decrease in tumoral tissue. This finding supports an endogenous function of CYP3A5 related to the metabolism of intra-prostatic androgens and cell growth, and that polymorphisms affecting CYP3A5 activity may result in altered prostate cancer risk and aggressiveness.
7
Raymond, Lendelle, Nikita Rayani, Grace Polson, Kylie Sikorski, Ailin Lian i Melissa A. VanAlstine-Parris. "Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver". Enzyme Research 2015 (9.11.2015): 1–4. http://dx.doi.org/10.1155/2015/321820.
Pełny tekst źródłaStreszczenie:
Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.
8
Chang, Thomas KH, i Rosita KY Yeung. "Effect of trans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5". Canadian Journal of Physiology and Pharmacology 79, nr 3 (1.03.2001): 220–26. http://dx.doi.org/10.1139/y00-130.
Pełny tekst źródłaStreszczenie:
Red wine concentrate has been reported to inhibit the catalytic activity of human recombinant cytochrome P450 (CYP) 3A4. Wine contains many polyphenolic compounds, including trans-resveratrol, which is also available commercially as a nutraceutical product. In the present study, we examined the in vitro effect of trans-resveratrol on human CYP3A catalytic activity by employing recombinant CYP3A4 and CYP3A5 as model enzymes and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) as a CYP3A substrate. Trans-resveratrol inhibited BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 in a concentration-dependent manner. In each case, the inhibition was noncompetitive, as determined by Lineweaver-Burk and Dixon plots of the enzyme kinetic data. The apparent Ki values (mean ± SEM) for the inhibition by trans-resveratrol of BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 were 10.2 ± 1.1 µM and 14.7 ± 0.3 µM, respectively. Preincubation of trans-resveratrol with NADPH and CYP3A4 or CYP3A5 for 10 or 15 min prior to initiation of substrate oxidation did not enhance the inhibitory effect, suggesting that this compound was not a mechanism-based inactivator of CYP3A4 or CYP3A5 when BFC was used as the substrate. Overall, our study provides the first demonstration that trans-resveratrol inhibits, in vitro, a substrate oxidation reaction catalyzed by human recombinant CYP3A4 and CYP3A5.Key words: 7-benzyloxy-4-trifluoromethylcoumarin, cytochrome P450, CYP3A4, CYP3A5, 7-hydroxy-4-trifluoromethylcoumarin, nutraceutical, trans-resveratrol.
9
Bořek-Dohalská, Lucie, i Marie Stiborová. "Cytochrome P450 3A activities and their modulation by α-naphthoflavone in vitro are dictated by the efficiencies of model experimental systems". Collection of Czechoslovak Chemical Communications 75, nr 2 (2010): 201–20. http://dx.doi.org/10.1135/cccc2009525.
Pełny tekst źródłaStreszczenie:
The knowledge on efficiencies of different in vitro systems containing cytochromes P450 (CYP) of a 3A subfamily is crucial to screen potential substrates of these CYPs. We evaluated and compared efficiencies of several in vitro CYP3A enzymatic systems to oxidize the model substrates, α-NF and testosterone, under the standardized experimental conditions. Five CYP3A systems were tested: (i) human hepatic microsomes rich in CYP3A4, (ii) hepatic microsomes of rabbits treated with a CYP3A6 inducer, rifampicine, (iii) microsomes of Baculovirus transfected insect cells containing recombinant human CYP3A4 and NADPH:CYP reductase with or without cytochrome b5 (SupersomesTM), (iv) membranes isolated from Escherichia coli, containing recombinant human CYP3A4, NADPH:CYP reductase and cytochrome b5, and (v) human CYP3A4 or rabbit CYP3A6 reconstituted with NADPH:CYP reductase with or without cytochrome b5 in liposomes. All systems oxidize testosterone to its 6β-hydroxylated metabolite and α-NF to trans-7,8-dihydrodiol and 5,6-epoxide. The most efficient systems oxidizing both compounds were CYP3A4-SupersomesTM containing cytochrome b5, followed by human hepatic microsomes. This finding suggests these systems to be suitable for general evaluating a variety of compounds as potential substrates of CYP3A4. The lowest efficiencies to oxidize α-NF and testosterone were found for CYP3A4 expressed in membranes of E. coli, and for reconstituted CYP3A4 or CYP3A6. Utilizing the tested enzymatic systems, we also explain here the discrepancies, which showed previously the controversial effects of α-NF on CYP3A-mediated reactions. We demonstrate that inhibition or stimulation of the CYP3A-mediated testosterone hydroxylation by α-NF is dictated by efficiencies of individual enzymatic systems to oxidize the CYP3A substrates.
10
Fang, Jim, i Jiuxue Song. "In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking". Journal of Pharmacy & Pharmaceutical Sciences 15, nr 4 (4.10.2012): 538. http://dx.doi.org/10.18433/j31w20.
Pełny tekst źródłaStreszczenie:
Purpose. The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP+) and reduced haloperidol pyridinium (RHP+). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural analogues of N-methyl-4-phenylpyridinium (MPP+), a well-known neurotoxin. RHP+ can be oxidized to HP+ by CYP1A1. In the current study, the oxidation of RHP+ to HP+ was investigated using human placenta microsomal preparations which contain relatively high levels of CYP1A1. Methods. Cytochrome P450 isoenzymes responsible for the metabolism of RHP+ were characterized in vitro using human placenta microsomal preparations from smokers and non-smokers. Results. A comparison of the metabolic activities between smokers and non-smokers suggests that smokers had higher activities for the oxidation of RHP+. A selective antibody against CYP1A1 was a partial inhibitor of RHP+ oxidase in placenta from smokers but had no effect in placenta from non-smokers. Furafylline and ketokonazole were shown to be stronger inhibitors of the oxidation of RHP+ to HP+ in liver than in placenta. This seems to indicate important contributions of CYP1A1 and CYP3A7 as compared to CYP1A2 and CYP3A4, respectively, because furafylline and ketokonazole are stronger inhibitors of CYP1A2 and CYP3A4 than CYP1A1 and CYP3A7, respectively. Interestingly, α-naphathoflavone enhanced the metabolic activity in liver microsomes due to its activator effect on CYP3A4. On the other hand, α-naphathoflavone partially inhibited the activity in placenta microsomes, indicating a role played by CYP1A1 or CYP1A2 in the oxidation of RHP+ in placenta. Conclusions. These data indicate that CYP1A1 plays an important role in the oxidation of RHP+ to HP+ in placenta from smokers. CYP3A7 and CYP3A4 could also play important roles in the metabolism of RHP+ in placenta microsomes.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
11
Saiz-Rodríguez, Miriam, Susana Almenara, Marcos Navares-Gómez, Dolores Ochoa, Manuel Román, Pablo Zubiaur, Dora Koller i in. "Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates". Biomedicines 8, nr 4 (22.04.2020): 94. http://dx.doi.org/10.3390/biomedicines8040094.
Pełny tekst źródłaStreszczenie:
Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.
12
Hermann, Marie Louise Hiort, i Mette Tingleff Skaanild. "Porcine foetal and neonatal CYP3A liver expression". Journal of Xenobiotics 1, nr 1 (6.05.2011): 1. http://dx.doi.org/10.4081/xeno.2011.e1.
Pełny tekst źródłaStreszczenie:
Human cytochrome P450 3A7 (CYP3A7) and cytochrome P450 3A4 (CYP3A4) are hepatic metabolising enzymes which participates in the biotransformation of endo- and exogenous substances in foetuses and neonates respectively. These CYP3A enzymes display an inverse relationship: CYP3A7 is the dominant enzyme in the foetal liver, whereas the expression of CYP3A4 is low. After parturition there is a shift in the expression, thus CYP3A7 is down regulated, while the level of CYP3A4 gradually increases and becomes the dominant metabolising CYP3A enzyme in the adult. The minipig is increasingly being used as a model for humans in biomedical studies, because of its many similarities with the human physiology and anatomy. The aim of this study was to examine whether, as in humans, a shift is seen in the hepatic expression of a CYP3A7- like enzyme to cytochrome P450 3A29 (CYP3A29) (an orthologue to the human CYP3A4) in minipigs. This was elucidated by examining the hepatic mRNA expression of CYP3A7 and CYP3A29 in 39 foetuses and newborn Göttingen minipigs using quantitative real time polymerase chain reaction (qPCR). Furthermore the immunochemical level of CYP3A7-LE and CYP3A29 was measured in liver microsomes using western blotting. The expression of CYP3A29 was approximately 9- fold greater in neonates compared to foetuses, and a similar difference was reflected on the immunochemical level. It was not possible to detect a significant level of foetal CYP3A7 mRNA, but immunoblotting showed a visible difference depending on age. This study demonstrates an increase in the expression of CYP3A29, the CYP3A4 orthologue in perinatal minipigs as in humans, which suggests that the minipig could be a good model when testing for human foetal toxicity towards CYP3A4 substrates.
13
Bogacz, Anna, Monika Karasiewicz, Karolina Dziekan, Danuta Procyk, Małgorzata Górska-Paukszta, Aleksandra Kowalska, Przemysław Ł. Mikołajczak, Marcin Ożarowski i Bogusław Czerny. "Impact of Panax ginseng and Ginkgo biloba extracts on expression level of transcriptional factors and xenobiotic-metabolizing cytochrome P450 enzymes". Herba Polonica 62, nr 1 (1.03.2016): 42–54. http://dx.doi.org/10.1515/hepo-2016-0004.
Pełny tekst źródłaStreszczenie:
Summary Introduction: Despite widespread use of Panax ginseng and Ginkgo biloba, the data on the safety as well as herb-drug interactions are very limited. Therefore, we postulate that P. ginseng and G. biloba may modulate the activity and content of cytochrome P450 isozymes involved in the biotransformation of diverse xenobiotic substances. Objective: The aim of our study was to determine the influence of herbal remedies on the expression level of CYP enzymes and transcriptional factors. Methods: Male Wistar rats were given standardized Panax ginseng (30 mg/kg p.o.) or standardized Ginkgo biloba (200 mg/kg p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by realtime PCR method. Results: Our results showed a decrease of CYP3A1 (homologue to human CYP3A4) mRNA level after P. ginseng extract treatment. The CYP2C6 (homologue to human CYP2C9) expression was also reduced. Additionally, after 10 days of the treatment with P. ginseng an increase of CYP1A1 (homologue to human CYP1A1) and CYP1A2 (homologue to human CYP1A2) expression was observed. Moreover, G. biloba extract also caused an increase of expression level for CYP1A1, CYP2C6, CYP3A1 and CYP3A2. Conclusion: Our findings suggest that herbal extracts can modulate the expression of transcriptional factors and CYP enzymes involved in xenobiotic metabolism and chemical carcinogenesis.
14
Williams, J. Andrew, Barbara J. Ring, Varon E. Cantrell, David R. Jones, James Eckstein, Kenneth Ruterbories, Mitchell A. Hamman, Stephen D. Hall i Steven A. Wrighton. "Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7". Drug Metabolism and Disposition 30, nr 8 (1.08.2002): 883–91. http://dx.doi.org/10.1124/dmd.30.8.883.
Pełny tekst źródła
15
Diekstra, Meta, Heinz Josef Klümpen, Martijn P. J. K. Lolkema, Huixin Yu, Jacqueline S. L. Kloth, Hans Gelderblom, Ron H. N. van Schaik i in. "Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): 4580. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4580.
Pełny tekst źródłaStreszczenie:
4580 Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.
16
Krusekopf, Solveigh, Ivar Roots i Ullrich Kleeberg. "Differential drug-induced mRNA expression of human CYP3A4 compared to CYP3A5, CYP3A7 and CYP3A43". European Journal of Pharmacology 466, nr 1-2 (kwiecień 2003): 7–12. http://dx.doi.org/10.1016/s0014-2999(03)01481-x.
Pełny tekst źródła
17
Salameh, Ghada, Kamal Al Hadidi i Mohammad El Khateeb. "Genetic polymorphisms of the CYP3A4, CYP3A5, CYP3A7 and CYP1A2 among the Jordanian population". Environmental Toxicology and Pharmacology 34, nr 1 (lipiec 2012): 23–33. http://dx.doi.org/10.1016/j.etap.2012.01.006.
Pełny tekst źródła
18
Novillo, Apolonia, Alicia Romero-Lorca, María Gaibar, Raoudha Bahri, Nourdin Harich, David Sánchez-Cuenca, Esther Esteban i Ana Fernández-Santander. "Genetic diversity of CYP3A4 and CYP3A5 polymorphisms in North African populations from Morocco and Tunisia". International Journal of Biological Markers 30, nr 1 (styczeń 2015): 148–51. http://dx.doi.org/10.5301/jbm.5000118.
Pełny tekst źródłaStreszczenie:
The genes CYP3A4 and CYP3A5 form part of a cluster of cytochrome P450 genes involved in drug metabolism reactions. The allelic variants of these genes CYP3A4*1B, CYP3A4*3, CYP3A4*17 and CYP3A5*3 have been linked both to the reduced catalytic activity of cytochromes and to prostate cancer risk in whites, though scarce data exist for North African populations. The main objective of this study was to describe CYP3A4*3, CYP3A4*17, CYP3A4*1B and CYP3A5*3 allele frequencies and haplotype variation in Moroccan Berbers and the general Tunisian population. The data obtained for the Tunisian participants were consistent with the European allele frequency ranges described, while Moroccan Berbers showed high frequencies of CYP3A4*17 (1.8%), CYP3A4*3 (8.5%) and the CYP3A4*1B/CYP3A5*3 haplotype (18.4%). This haplotype, linked to an increased risk of prostate cancer, was detected at a much higher frequency compared with the present Tunisian population (8.4%) or with reported frequencies for populations such as whites (0.6%) or African Americans (5.3%).
19
Roberts, Jessica K., Chad D. Moore, Erin G. Romero, Robert M. Ward, Garold S. Yost i Christopher A. Reilly. "Regulation of CYP3A genes by glucocorticoids in human lung cells". F1000Research 2 (13.08.2013): 173. http://dx.doi.org/10.12688/f1000research.2-173.v1.
Pełny tekst źródłaStreszczenie:
Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
20
Roberts, Jessica K., Chad D. Moore, Erin G. Romero, Robert M. Ward, Garold S. Yost i Christopher A. Reilly. "Regulation of CYP3A genes by glucocorticoids in human lung cells". F1000Research 2 (8.10.2013): 173. http://dx.doi.org/10.12688/f1000research.2-173.v2.
Pełny tekst źródłaStreszczenie:
Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
21
Huang, Lingfei, Junyan Wang, Jufei Yang, Huifen Zhang, Yinghua Ni, Zhengyi Zhu, Huijuan Wang i in. "Impact of CYP3A4/5 and ABCB1 polymorphisms on tacrolimus exposure and response in pediatric primary nephrotic syndrome". Pharmacogenomics 20, nr 15 (październik 2019): 1071–83. http://dx.doi.org/10.2217/pgs-2019-0090.
Pełny tekst źródłaStreszczenie:
Aim: To evaluate the impact of CYP3A4*1G, CYP3A5*3 and ABCB1-C3435T polymorphisms on tacrolimus concentrations, efficacy and tolerance in pediatric primary nephrotic syndrome. Methods: Dose-adjusted concentrations (C0/D), daily dose, frequency and time to relapse, cumulative remission days, and adverse reactions in 65 Chinese patients with various genotypes were retrospectively collected and compared. Results: C0/D increased in CYP3A4*1/*1, CYP3A5*3/*3 and CYP3A4*1/*1-3A5*3/*3 diplotype carriers by 38.4, 69.7 and 40.9% compared with CYP3A4*1/*1G, CYP3A5*1/*3 and noncarriers, respectively. Recurrence risks were decreased in CYP3A4*1/*1 (0.43 of hazard ratio to *1/*1G) and CYP3A5*3/*3 carriers (0.43 of hazard ratio to *1/*3). None of polymorphisms was linked to adverse reactions. Conclusion: The genotypes of CYP3A4*1G and CYP3A5*3 rather than ABCB1-C3435T potentially predicted tacrolimus exposure and clinical response in pediatric primary nephrotic syndrome.
22
Elens, Laure, Rachida Bouamar, Dennis A. Hesselink, Vincent Haufroid, Ilse P. van der Heiden, Teun van Gelder i Ron HN van Schaik. "A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients". Clinical Chemistry 57, nr 11 (1.11.2011): 1574–83. http://dx.doi.org/10.1373/clinchem.2011.165613.
Pełny tekst źródłaStreszczenie:
BACKGROUND Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes. METHODS We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study). RESULTS The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, −46% to −20%; P = 0.018). When combined with the *3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A5*3/*3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A5*3/*3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A5*1 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A5*3/*3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A5*3/*3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A5*1 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A5*1. CONCLUSIONS The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.
23
Ün, İsmail, İ. Ömer Barlas, Nisa Uyar, Bahar Taşdelen i Naci Tiftik. "Distribution of drug-metabolizing enzymes coding genes CYP2D6, CYP3A4, CYP3A5 alleles in a group of healthy Turkish population". Turkish Journal of Biochemistry 44, nr 2 (9.07.2018): 142–46. http://dx.doi.org/10.1515/tjb-2017-0226.
Pełny tekst źródłaStreszczenie:
Abstract Objective: Variant alleles in specific ethnic groups are important for personalized drug therapy regimens and adverse drug reactions. Therefore, the aim of this study was to investigate allelic frequencies of the CYP2D6*1, CYP3A4*5, CYP3A4*18, CYP3A5*2 and CYP3A5*4 in a group of Turkish population. Materials and methods: Three hundred and six unrelated healthy subjects who were accepted as blood donors to the Mersin University Blood Bank were included in the study after informed consent. Allelic frequencies of the CYP2D6*1 (rs3892097), CYP3A4*5 (rs55901263), CYP3A4*18 (rs28371759), CYP3A5*2 (rs28365083) and CYP3A5*4 (rs56411402) were determined by using polymerase chain reaction-restriction fragment length polymorphism assays. Results: CYP2D6 allele frequencies in detected group was 100% for CYP2D6*1 (WT/WT). CYP3A4 allele frequencies of subjects were 100% for CYP3A4*5 (C/C) and CYP3A4*18 (T/T). CYP3A5 allele were in Hardy-Weinberg equilibrium for CYP3A5*2 (p=0.142) and frequencies for C and A allele were 91% and 9% respectively. CYP3A5 allele frequencies of subjects was 100% for CYP3A5*4 (WT/WT). Conclusion: Screening of low frequency alleles by pharmacogenetic testing must not be omitted to optimize pharmacotherapy and avoid severe drug toxicities. Frequency distributions of the identified polymorphisms in the present study may contribute to the personalized drug therapy regimens and prediction of possible adverse drug reactions in the Turkish population.
24
Resál, T., K. Farkas i T. Molnár. "P546 The safety and efficacy of the new-generation budesonide-MMX in the aspect of the cytochrome P-450 enzyme genotype". Journal of Crohn's and Colitis 15, Supplement_1 (1.05.2021): S516. http://dx.doi.org/10.1093/ecco-jcc/jjab076.667.
Pełny tekst źródłaStreszczenie:
Abstract Background Unlike previous forms of budesonide absorbing from the ileal and ascending colon region, the new-generation budesonide-MMX contains a formula, that allows absorption throughout the whole colon. Budesonide is degraded in the liver by cytochrome P450 3A enzyme, but so far, there is no study examining the relationship between the budesonide’s effect and the enzyme activity. CYP3A5 is absent in 90% of the European/caucasian population due to a functional loss mutation (CYP3A5*3), whereas patients with the wild-type CYP3A5*1 allele may be expected to have increased metabolism. The most common genetic polymorphisms in CYP3A4 (CYP3A4*1B and CYP3A4*22) result in increased and decreased expression, respectively. Methods We enrolled 33 patients with UC in this prospective study until January of 2021. Patients received 9 mg oral budesonide-MMX once daily until 8 weeks. Laboratory parameters (cholesterol, triglyceride, CRP) and serum hormone levels (parathormone, dehydroepiandrosterone and cortisol) were monitored before and after the 8-week therapy to follow metabolic and hormonal changes. During these visits, body composition analysis was also performed with InBody 770 machine to observe the adverse effects of budesonide-MMX in respect of body fat mass, body mass index, protein content of the body and bone mineral content. We examined the CYP450 3A (CYP3A5 and CYP3A4) enzyme genotype of the patients, to see, whether the different alleles of this drug-degrading enzyme affect the efficacy and safety. Results 33 patients had received the 2-month therapy. By the end of follow-up, based on partial Mayo score, 26 (78.8%) patients experienced remission and 6 patients (18.2%) were primary non-responders. Mean pMayo score decreased from 4.18 to 1.63 (p<0.001). No significant changes were observable regarding body composition. Serum cholesterol level showed significant increase (p<0.001), while triglyceride and CRP did not show significant changes. Serum cortisol levels were decreased (p<0.001), while PTH and DHEA showed no significant decrease. Only two patients experienced side effects: one of them hypertonia, headache and acnes, while the other mild diarrhoea. 3 patients have CYP3A5*1/*3 genotype, and 16 have CYP3A5*3/*3. There was no significant difference between the two groups, regarding safety and efficacy. Only 1 patient have CYP3A4*1B genotype, while the rest have CYP3A4*1, hence, no statistics could be performed. Conclusion In our study, budesonide-MMX proved to be safe and effective in the therapy of UC, however, cholesterol was elevated in the serum. Based on our cohort, different genotypes of CYP3A don’t have an impact on the effect of the drug, however, CYP3A allele variants are rare, therefore, further examinations should be performed.
25
R Jada, S., X. Xiang, Q. Zhou, H. H Li, L. L Ooi i B. Chowbay. "Hepatic expression of CYP3A4 and CYP3A5 genes in Asians and implications for pharmacokinetic variations during chemotherapy". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 13124. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13124.
Pełny tekst źródłaStreszczenie:
13124 Background: Hepatic expression of CYP3A4 and CYP3A5 enzymes are important determinants of interindividual variability in chemotherapy. The objective of this study was to genotypically quantitate expression of CYP3A4 and CYP3A5 genes in healthy hepatic tissues from Asian cancer patients undergoing hepatectomy. Methods: Healthy Asian hepatic tissues (Chinese: N = 27; Malay: N = 1; Indian: N = 3) were obtained from the institution’s central tissue repository bank. Messenger RNA was isolated from each tissue sample and reversed transcribed to cDNA followed by real time PCR experiments. Results from these gene expression experiments were normalized against GAPDH transcripts. DNA was also extracted from the hepatocytes and genotyped for four single nucleotide polymorphisms in the CYP3A4 gene (CYP3A4*1B, *4, *5 and *6) and three in the CYP3A5 gene (CYP3A5*1, *3 and *6). Results: CYP3A4 variant forms were absent in all Asian patients. CYP3A5 was polymorphic and genotyping analysis showed that the *1/*1, *1/*3 and *3/*3 genotypes were present in 6%, 52% and 42% of the Asian liver samples, respectively. Liver tissues harbouring the *1/*1 and *1/*3 genotypes showed insignificant CYP3A5 expression pattern (P=0.160). The CYP3A5 mRNA expression levels were approximately 6-fold lower in *3/*3 samples compared with samples carrying at least one *1 allele (*1/*1 + *1/*3). Non-parametric analysis using Kruskal-Wallis test showed that the hepatic expression of CYP3A5 mRNA between liver tissues that harboured at least one *1 allele (*1/*1 + *1/*3) and those carrying homozygous *3/*3 genotype to be highly significantly different (P < 0.007). Conclusions: These results show that polymorphic CYP3A4 isoforms are probably rare in Asians compared with CYP3A5 polymorphisms. This study also suggest that CYP3A5, rather than CYP3A4 could be important for interindividual variations in pharmacokinetics of CYP3A4/5 substrates during chemotherapy in Asians. No significant financial relationships to disclose.
26
Bellah, Sm Faysal, Maizbha Uddin Ahmed, Sikder Nahidul Islam Rabbi, Mohd Nazmul Hasan Apu, Md Siddiqul Islam, Mir Muhammad Nasir Uddin, Mohammad Safiqul Islam i Abul Hasnat. "Prostate Cancer Risk in Relation to CYP3A4 and CYP3A5 Genotypes in the Bangladeshi Population". Dhaka University Journal of Pharmaceutical Sciences 14, nr 2 (28.06.2016): 179–85. http://dx.doi.org/10.3329/dujps.v14i2.28508.
Pełny tekst źródłaStreszczenie:
Genetic polymorphism on CYP3A4 and CYP3A5 gene and their associational susceptibility to prostate cancer was studied on Bangladeshi population, considering the importance of CYP3A4 and CYP3A5 gene in detoxification of xenobiotics from physiological territory. In this case control regulated study, we focused on two allelic variants CYP3A4 rs2740574 (CYP3A4*1B) and CYP3A5 rs776746 (CYP3A5*3) applying Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP). Associational risk on prostate cancer was estimated as odds ratio (OR) and 95% confidence interval (CI) using unconditional logistic regression models. An elevated prostate cancer risk was found with heterozygous, mutant and heterozygous plus mutant variants of CYP3A4*1B which is not statistically significant (p>0.05), whereas a significant association was found with heterozygous, mutant and heterozygous plus mutant variants of CYP3A5*3 (OR =4.36, 95%CI = 1.53 to 12.38, P =0.003; OR =3.85, 95%CI = 1.19 to 12.43, P = 0.017 and OR =4.13, 95%CI = 1.84 to 9.28, p =0.0006 respectively). The findings signposted a significant association of CYP3A5*3 gene and nullify the association of CYP3A4*1B genes polymorphism with prostate cancer risk in Bangladeshi subject.Dhaka Univ. J. Pharm. Sci. 14(2): 179-185, 2015 (December)
27
El-Shair, Sahar, Mohammad Al Shhab, Khaled Zayed, Moaath Alsmady i Malek Zihlif. "Association Between CYP3A4 and CYP3A5 Genotypes and Cyclosporine's Blood Levels and Doses among Jordanian Kidney Transplanted Patients". Current Drug Metabolism 20, nr 8 (24.09.2019): 682–94. http://dx.doi.org/10.2174/1389200220666190806141825.
Pełny tekst źródłaStreszczenie:
Background: Cyclosporine is used as an immunosuppressive agent in kidney transplantation. It has a narrow therapeutic window. Cyclosporine is predominantly metabolized by CYP3A4 and CYP3A5. The most common Single Nucleotide Polymorphisms (SNPs) affecting cyclosporine metabolism (CYP3A4*1B, CYP3A4*1G, CYP3A4*22 and CYP3A5*3) were investigated among Jordanian kidney transplanted patients to find out the genotypes and allele frequencies of these SNPs. Additionally, this study investigated whether genotypes of CYP3A4 and CYP3A5 affect C2 blood levels, dosing of cyclosporine and the prevalence of acute rejection. Methods: Blood samples of 109 adult patients taking cyclosporine as their primary immunosuppressant for kidney transplantation were collected from the Prince Hamzah Hospital, Amman, Jordan. Patients’ first C2 blood levels and their first two given doses were collected. Patients were genotyped for the four SNPs using Polymerase Chain Reaction- restriction Fragment Length Polymorphism (PCR-RFLP) assay method. Results: Allele frequencies among Jordanian patients for CYP3A4*1B, CYP3A4*1G, CYP3A4*22 and CYP3A5*3 were 0.037, 0.399, 0.037 and 0.271, respectively. There was a significant association between CYP3A4*22 and mean difference in the second and first given doses (P=0.034). There was a big difference between CYP3A4*22 and the mean of the first C2 blood levels (P=0.063). Conclusion: There was a strong association between CYP3A4*22 and the mean difference between the second and first given doses. There was a trend of significant difference between the mean of the first C2 blood levels among heterozygous CYP3A4*22 patients. Pharmacogenomics may hold promise in assisting the prediction of the best cyclosporine dose and C2 blood level among Jordanian kidney transplant patients.
28
KIVISTÖ, KARI T., GERHARD BOOKJANS, MARTIN F. FROMM, ERNST-ULRICH GRIESE, PETER MÜNZEL i HEYO K. KROEMER. "Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue". British Journal of Clinical Pharmacology 42, nr 3 (wrzesień 1996): 387–89. http://dx.doi.org/10.1046/j.1365-2125.1996.42615.x.
Pełny tekst źródła
29
Goh, Boon-Cher, Soo-Chin Lee, Ling-Zhi Wang, Lu Fan, Jia-Yi Guo, Jatinder Lamba, Erin Schuetz i in. "Explaining Interindividual Variability of Docetaxel Pharmacokinetics and Pharmacodynamics in Asians Through Phenotyping and Genotyping Strategies". Journal of Clinical Oncology 20, nr 17 (1.09.2002): 3683–90. http://dx.doi.org/10.1200/jco.2002.01.025.
Pełny tekst źródłaStreszczenie:
PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1. RESULTS: Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5′ regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients. CONCLUSION: Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.
30
Hsu, Mei-Hui, i Eric F. Johnson. "Active-site differences between substrate-free and ritonavir-bound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4". Journal of Biological Chemistry 294, nr 20 (29.03.2019): 8015–22. http://dx.doi.org/10.1074/jbc.ra119.007928.
Pełny tekst źródłaStreszczenie:
Cytochrome P450 (CYP) 3A4 is a major contributor to hepatic drug and xenobiotic metabolism in human adults. The related enzyme CYP3A5 is also expressed in adult liver and has broader age and tissue distributions. However, CYP3A5 expression is low in most Caucasians because of the prevalence of an allele that leads to an incorrectly spliced mRNA and premature termination of translation. When expressed, CYP3A5 expands metabolic capabilities and can augment CYP3A4-mediated drug metabolism, thereby reducing drug efficacy and potentially requiring dose adjustments. The extensive role of CYP3A4 in drug metabolism reflects in part the plasticity of the substrate-free enzyme to enlarge its active site and accommodate very large substrates. We have previously shown that the structure of the CYP3A5–ritonavir complex differs substantially from that of the CYP3A4–ritonavir complex. To better understand whether these differences are conserved in other CYP3A5 structures and how they relate to differential plasticity, we determined the X-ray crystallographic structure of the CYP3A5 substrate-free complex to 2.20 Å resolution. We observed that this structure exhibits a much larger active site than substrate-free CYP3A4 and displays an open substrate access channel. This reflected in part a lower trajectory of the helix F–F′ connector in CYP3A4 and more extensive π–CH interactions between phenylalanine residues forming the roof of the active-site cavity than in CYP3A5. Comparison with the CYP3A5–ritonavir complex confirmed conserved CYP3A5 structural features and indicated differences in plasticity between CYP3A4 and CYP3A5 that favor alternative ritonavir conformations.
31
Du, Jing, Lan Yu, Lei Wang, Aiping Zhang, Anli Shu, Lingyun Xu, Mingsheng Xu i in. "Differences in CYP3A4⁎1G genotype distribution and haplotypes of CYP3A4, CYP3A5 and CYP3A7 in 3 Chinese populations". Clinica Chimica Acta 383, nr 1-2 (sierpień 2007): 172–74. http://dx.doi.org/10.1016/j.cca.2007.04.027.
Pełny tekst źródła
32
Nowak, Jan Krzysztof, Bartłomiej Bancerz i Alicja Bartkowska-Śniatkowska. "CYP3A drug metabolism in the developmental age: recent advances". Journal of Medical Science 88, nr 1 (12.03.2019): 58–61. http://dx.doi.org/10.20883/jms.2019.290.
Pełny tekst źródłaStreszczenie:
Background. The 3A subfamily of cytochrome P450 (CYP3A) accomplishes phase I metabolism for approximately half of the available medications. We aimed to review the recent advances in our understanding of CYP3A activity, which could apply to infants and toddlers.Material and Methods. A literature review.Results. The reviewed recent data cover: CYP3A7 expression and functions, changes of CYP3A4 function in the first two years of life, CYP3A intestinal metabolism and zonation, CYP3A metabolic programming, pediatric CYP3A pharmacogenetics, the impact of critical illness on CYP3A, phenotyping, and other clinical implications of a better comprehension of CYP3A biology.Conclusions. Although the knowledge of CYP3A enzymes has already changed pediatric practice, much more is to be expected in the upcoming years. The areas to watch include: endogenous markers for phenotyping, new CYP3A7 substrates and products, pharmacogenetic interactions with transporter genes for non‑immunomodulatory drugs, as well as interactions with microbiota and specific bioactive foodstuffs.
33
Zhang, Jiang-Wei, Yong Liu, Jie Cheng, Wei Li, Hong Ma, Hong-Tao Liu, Jie Sun i in. "Inhibition of Human Liver Cytochrome P450 by Star Fruit Juice". Journal of Pharmacy & Pharmaceutical Sciences 10, nr 4 (12.10.2007): 496. http://dx.doi.org/10.18433/j30593.
Pełny tekst źródłaStreszczenie:
Purpose. To examine the inhibitory effects of star fruit (Averrhoa carambola) juice towards seven major cytochrome P450 (CYP) isoforms and NADPH-cytochrome P450 reductase (CPR). Methods. The inhibitory effects of star fruit juice (0.5 to 5%, v/v) against the activities of seven CYP isoforms including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4 and CPR were examined in human liver microsomes. To identify time-dependent inhibition, star fruit juice (2.5%, v/v) was preincubated with microsomes and a NADPH-generating system for 0-15 min, and then the extent of inhibition towards seven CYP isoforms were examined. Results. Star fruit juice (5.0%, v/v) was found to inhibit all the activities of CYP isoforms tested by more than 70%. Based on the half inhibition values (%, v/v), the inhibitory effects towards different CYP isoforms were in the following order: CYP2A6 (0.9) > CYP1A2 (1.4) > CYP2D6 (1.6) > CYP2E1 (2.0) > CYP2C8 (2.2) > CYP2C9 (3.0) > CYP3A4 (3.2). Time-dependent inhibition was not observed towards any of the tested CYP isoforms. In addition, star fruit juice was found not to inhibit the activity of CPR. Conclusions. Star fruit juice inhibited the seven CYP isoforms tested, with the strongest inhibitory effect against CYP2A6 and the least towards CYP3A4.
34
He, Qingfeng, Fengjiao Bu, Hongyan Zhang, Qizhen Wang, Zhijia Tang, Jing Yuan, Hai-Shu Lin i Xiaoqiang Xiang. "Investigation of the Impact of CYP3A5 Polymorphism on Drug–Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling". Pharmaceuticals 14, nr 3 (27.02.2021): 198. http://dx.doi.org/10.3390/ph14030198.
Pełny tekst źródłaStreszczenie:
Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.
35
Yu, Ai-Ming, Katsumi Fukamachi, Kristopher W. Krausz, Connie Cheung i Frank J. Gonzalez. "Potential Role for Human Cytochrome P450 3A4 in Estradiol Homeostasis". Endocrinology 146, nr 7 (1.07.2005): 2911–19. http://dx.doi.org/10.1210/en.2004-1248.
Pełny tekst źródłaStreszczenie:
Abstract Previously, a human CYP3A4-transgenic (Tg-CYP3A4) mouse line was reported to exhibit enhanced metabolism of midazolam by cytochrome P450 3A4 (CYP3A4) expressed in small intestine. Here we show that expression of CYP3A4 and murine cyp3a and cyp2b was both age and sex dependent. CYP3A4 was expressed in the livers of male and female Tg-CYP3A4 mice at 2 and 4 wk of age. Since 6 wk, CYP3A4 was undetectable in male livers, whereas it was constitutively expressed in female livers at decreased levels (3- to 5-fold). Pregnenolone 16α-carbonitrile markedly induced hepatic CYP3A4 expression, and the level was higher in females than males. Induction of intrinsic murine cyp3a and cyp2b was also sex dependent. Tg-CYP3A4 females were found to be deficient in lactation, leading to a markedly lower pup survival. The mammary glands of the Tg-CYP3A4 lactating mothers had underdeveloped alveoli with low milk content. Furthermore, β-casein and whey acidic protein mRNAs were expressed at markedly lower levels in Tg-CYP3A4 pregnant and nursing mouse mammary glands compared with wild-type mice. This impaired lactation phenotype was associated with significantly reduced serum estradiol levels in Tg-CYP3A4 mice. A pharmacokinetic study revealed that the clearance of iv administrated [3H]estradiol was markedly enhanced in Tg-CYP3A4 mice compared with wild-type mice. These results suggest that CYP3A4 may play an important role in estradiol homeostasis. This may be of concern for treatment of pregnant and lactating women because CYP3A4 gene expression and enzymatic activity can be potentially modified by CYP3A4 inhibitors or inducers in medications, supplements, beverages, and diet.
36
Indra, Radek, Katarína Vavrová, Petr Pompach, Zbyněk Heger i Petr Hodek. "Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b5 Activity". Biomedicines 8, nr 12 (28.11.2020): 547. http://dx.doi.org/10.3390/biomedicines8120547.
Pełny tekst źródłaStreszczenie:
Herein, the in vitro metabolism of tyrosine kinase inhibitor cabozantinib, the drug used for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma, was studied using hepatic microsomal samples of different human donors, human recombinant cytochromes P450 (CYPs), flavin-containing mono-oxygenases (FMOs) and aldehyde oxidase. After incubation with human microsomes, three metabolites, namely cabozantinib N-oxide, desmethyl cabozantinib and monohydroxy cabozantinib, were detected. Significant correlations were found between CYP3A4 activity and generation of all metabolites. The privileged role of CYP3A4 was further confirmed by examining the effect of CYP inhibitors and by human recombinant enzymes. Only four of all tested human recombinant cytochrome P450 were able to oxidize cabozantinib, and CYP3A4 exhibited the most efficient activity. Importantly, cytochrome b5 (cyt b5) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b5 also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b5. Since CYP3A4 exhibits high expression in the human liver and was found to be the most efficient enzyme in cabozantinib oxidation, we examined the kinetics of this oxidation. The present study provides substantial insights into the metabolism of cabozantinib and brings novel findings related to cabozantinib pharmacokinetics towards possible utilization in personalized medicine.
37
DeJonge, M., M. M. Woo, D. Van der Biessen, P. Hamberg, S. Sharma, L. C. Chen, N. Myke, L. Zhao, S. Hirawat i J. Verweij. "A drug interaction study between ketoconazole and panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 2501. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2501.
Pełny tekst źródłaStreszczenie:
2501 Background: The effects of ketoconazole (keto), a potent CYP3A inhibitor, on the pharmacokinetics (PK) of panobinostat (PAN) were investigated in an open-label, multicenter, cross-over, single sequence study. Methods: Patients (pts) with advanced solid tumors or NHL received single-agent PAN at 20 mg on Day 1 and single-agent keto at 400 mg daily on Days 5–9. On Day 8, PAN 20 mg was administered 1 hour after keto. All pts had adequate organ function and ECOG performance status <2. Serial plasma samples were collected for PAN PK evaluations on Days 1 and 8 and pre- and post-dose keto samples on Days 5, 8, and 9. Plasma PAN and keto concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Genotyping analysis of CYP3A4*1B, CYP3A5*2, *3, *6 and *7 were performed by using AmpliChip CYP450. Results: Fourteen Caucasian patients (9M, 5F) were enrolled with a median age of 59. Fourteen pts had homozygous wide-type CYP3A4*1A genotype, 11 pts had homozygous CYP3A5*3, and three pts had heterozygous CYP3A5*1/*3 genotype. No residual PAN concentrations were detected in pre-dose samples on Day 8. PAN PK parameters were calculated as either mean (CV%), median [range] or ratio (see Table). Single-dose PAN did not affect keto concentrations. Co-administration of keto and PAN increased PAN Cmax and AUC by 1.6- and 1.7-fold, respectively, but with no change in Tmax. There was no apparent difference in PAN PK between pts who carried CYP3A5*1 allele and homozygous CYP3A5*3 carriers. Conclusions: The less than 2-fold increase in PAN AUC upon co-administration suggests that CYP3A contribution to the total clearance of PAN is low. The observed interaction is not considered clinically relevant, as PAN doses are at least 2-fold greater than 20 mg (40 and 60 mg) have been safely administered in pts. CYP3A4 inhibitors should have no major impact on the exposure of PAN and may be co-administered when medically necessary. [Table: see text] [Table: see text]
38
Seo, Hyung-Ju, Seung-Bae Ji, Sin-Eun Kim, Gyung-Min Lee, So-Young Park, Zhexue Wu, Dae Sik Jang i Kwang-Hyeon Liu. "Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes". Pharmaceutics 13, nr 3 (10.03.2021): 371. http://dx.doi.org/10.3390/pharmaceutics13030371.
Pełny tekst źródłaStreszczenie:
Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s.
39
Gnedenko, O. V., A. S. Ivanov, E. O. Yablokov, S. A. Usanov, D. V. Mukha, G. V. Sergeev, A. V. Kuzikov i in. "Protein-protein interactions of cytochromes P450 3A4 and 3A5 with their intermediate redox partners cytochromes". Biomeditsinskaya Khimiya 60, nr 1 (styczeń 2014): 17–27. http://dx.doi.org/10.18097/pbmc20146001017.
Pełny tekst źródłaStreszczenie:
Molecular interactions between proteins redox partners (cytochromes Р450 3А4, 3А5 and cytochrome b ) within the monooxygenase system, which is known to be involved in drug biotransformation, were investigated. Human cytochromes Р450 3А4 and 3А5 (CYP3A4 and CYP3A5) form complexes with various cytochromes b : the microsomal ( b5mc ) and mitochondrial ( b5om ) forms of this protein, as well as with 2 “chimeric” proteins, b5(om-mc) , b5(mc-om) . Kinetic constants and equilibrium dissociation constants were determined by the SPR biosensor. Essential distinction between CYP3A4 and CYP3A5 was only observed upon their interactions with cytochrome b5om . Electroanalytical characteristics of electrodes with immobilized hemoproteins were obtained. The electrochemical analysis of CYP3A4, CYP3A5, b5mc, b5om , b5(om-mc) , and b5(mc-om) immobilized on screen printed graphite electrodes modified with membranous matrix revealed that these proteins have very close reduction potentials -0.435- -0.350 V (vs. Ag/AgCl). Cytochrome b mc was shown to be capable of stimulating the electrocatalytic activity of CYP3A4 to testosterone.
40
Gnedenko, O. V., A. S. Ivanov, E. O. Yablokov, S. A. Usanov, D. V. Mukha, G. V. Sergeev, A. V. Kuzikov i in. "Protein-protein interactions of cytochromes P450 3A4 and 3A5 with their intermediate redox partners cytochromes b5". Biomeditsinskaya Khimiya 61, nr 4 (2015): 468–74. http://dx.doi.org/10.18097/pbmc20156104468.
Pełny tekst źródłaStreszczenie:
Molecular interactions between proteins redox partners (cytochromes Р450 3А4, 3А5 and cytochrome b5) within the monooxygenase system, which is known to be involved in drug biotransformation, were investigated. Human cytochromes Р450 3A4 and 3А5 (CYP3A4 and CYP3A5) form complexes with various cytochromes b5: the microsomal (b5mc) and mitochondrial (b5om) forms of this protein, as well as with 2 “chimeric” proteins, b5(om-mc), b5(mc-om). Kinetic constants and equilibrium dissociation constants were determined by the SPR biosensor. Essential distinction between CYP3A4 and CYP3A5 was only observed upon their interactions with cytochrome b5om. Electroanalytical characteristics of electrodes with immobilized hemoproteins were obtained. The electrochemical analysis of CYP3A4, CYP3A5, b5mc, b5om, b5(om-mc), and b5(mc-om) immobilized on screen printed graphite electrodes modified with membranous matrix revealed that these proteins have very close reduction potentials -0.435 -0.350 V (vs. Ag/AgCl). Cytochrome b5mc was shown to be capable of stimulating the electrocatalytic activity of CYP3A4 in the presence of its substrate testosterone.
41
Furuse, Maizumi, Shuhei Hosomi, Yu Nishida, Shigehiro Itani, Yuji Nadatani, Shusei Fukunaga, Koji Otani i in. "The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients". PLOS ONE 16, nr 4 (22.04.2021): e0250597. http://dx.doi.org/10.1371/journal.pone.0250597.
Pełny tekst źródłaStreszczenie:
Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.
42
Mutawi, Thuraya M., Mohamed M. Zedan, Raida S. Yahya, Mahmoud M. Zakria, Mamdouh R. El-Sawi i Andrea Gaedigk. "Genetic variability of CYP2D6, CYP3A4 and CYP3A5 among the Egyptian population". Pharmacogenomics 22, nr 6 (kwiecień 2021): 323–34. http://dx.doi.org/10.2217/pgs-2020-0140.
Pełny tekst źródłaStreszczenie:
Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods: CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.
43
Ji, Seung-Bae, So-Young Park, Subin Bae, Hyung-Ju Seo, Sin-Eun Kim, Gyung-Min Lee, Zhexue Wu i Kwang-Hyeon Liu. "Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes". Pharmaceutics 13, nr 9 (7.09.2021): 1419. http://dx.doi.org/10.3390/pharmaceutics13091419.
Pełny tekst źródłaStreszczenie:
The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.
44
Kohlrausch, Fabiana B., Ángel Carracedo i Mara H. Hutz. "Characterization of CYP1A2, CYP2C19, CYP3A4 and CYP3A5 polymorphisms in South Brazilians". Molecular Biology Reports 41, nr 3 (18.01.2014): 1453–60. http://dx.doi.org/10.1007/s11033-013-2990-8.
Pełny tekst źródła
45
Ma, Wenjuan, Wei Wang, Xuhua Huang, Guangzhe Yao, Qi Jia, Jiayuan Shen, Huizi Ouyang, Yanxu Chang i Jun He. "HPLC-MS/MS Analysis of Aconiti Lateralis Radix Praeparata and Its Combination with Red Ginseng Effect on Rat CYP450 Activities Using the Cocktail Approach". Evidence-Based Complementary and Alternative Medicine 2020 (9.03.2020): 1–12. http://dx.doi.org/10.1155/2020/8603934.
Pełny tekst źródłaStreszczenie:
Red ginseng is often combined with Aconiti Lateralis Radix Praeparata to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as compared to the singular use of either herb. The purpose of this study was to investigate the effect of Aconiti Lateralis Radix Praeparata and its combination with red ginseng on the activities of CYP450 enzymes in rats. A sensitive and reliable HPLC-MS/MS method was established and validated for the simultaneous determination of eight probe drugs, phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), dapsone (CYP3A4), 7-hydroxycoumarin (CYP2A6), bupropion (CYP2B6), and amodiaquine (CYP2C8), in rat plasma using diazepam as internal standard (IS). The chromatographic separation was performed on a Waters XBridge™ C18 column (2.1 mm × 100 mm, 3.5 μm) using a gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. The method was successfully applied in evaluating the effect of Aconiti Lateralis Radix Praeparata and red ginseng on the activities of CYP450 enzymes. The pharmacokinetic results of the eight probe drugs suggested that Aconiti Lateralis Radix Praeparata may inhibit the activity of CYP2A6, CYP2C19, CYP2B6, CYP1A2, CYP3A4, and CYP2C9 enzymes in rats. Comparison between the two groups, Aconiti Lateralis Radix Praeparata combined with red ginseng and Aconiti Lateralis Radix Praeparata, indicated that red ginseng may inhibit the activity of CYP2D6 and CYP2B6 enzymes while inducing the activity of CYP1A2, CYP3A4, and CYP2C9 enzymes.
46
Doshi, Utkarsh, i Albert P. Li. "Luciferin IPA–Based Higher Throughput Human Hepatocyte Screening Assays for CYP3A4 Inhibition and Induction". Journal of Biomolecular Screening 16, nr 8 (10.08.2011): 903–9. http://dx.doi.org/10.1177/1087057111414900.
Pełny tekst źródłaStreszczenie:
The authors report here higher throughput screening (HTS) assays for the evaluation of CYP3A4 inhibition and CYP3A4 induction in human hepatocytes using a novel CYP3A4 substrate, luciferin IPA (LIPA). Using human recombinant CYP450 isoforms, LIPA was found to be metabolized extensively by CYP3A4 but not by CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. In the 384-well plate CYP3A4 inhibition assay, the known inhibitors 1-aminobenzotriazole, erythromycin, ketoconazole, and verapamil were found to cause extensive (maximum inhibition of >80%), dose-dependent, statistically significant inhibition of LIPA metabolism. The non-CYP3A4 inhibitors diethyldithiocarbamate, quercetin, quinidine, sulfaphenazole, ticlopidine, and tranylcypromine were found to have substantially lower (maximum inhibition of <50%) or no apparent inhibitory effects in the HTS assay. In the 96-well plate induction assay, the CYP3A4 inducers rifampin, phenobarbital, carbamazepine, phenytoin, troglitazone, rosiglitazone, and pioglitazone yielded dose-dependent induction of LIPA metabolism, whereas the CYP1A2 inducers omeprazole and 3-methylcholanthrene did not display any induction in the CYP3A4 activity. The high sensitivity and specificity of the assays, the relative ease of execution, and reduced cost, time, and test material requirements suggest that the HTS assays may be applied routinely for screening a large number of chemicals in the drug discovery phase for CYP3A4 inhibitory and inducing potential.
47
Tseng, Elaine, Robert L. Walsky, Ricardo A. Luzietti, Jennifer J. Harris, Rachel E. Kosa, Theunis C. Goosen, Michael A. Zientek i R. Scott Obach. "Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)". Drug Metabolism and Disposition 42, nr 7 (15.04.2014): 1163–73. http://dx.doi.org/10.1124/dmd.114.057000.
Pełny tekst źródła
48
Sugimoto, Mitsushige, Daiki Hira, Masaki Murata, Takashi Kawai i Tomohiro Terada. "Effect of Antibiotic Susceptibility and CYP3A4/5 and CYP2C19 Genotype on the Outcome of Vonoprazan-Containing Helicobacter pylori Eradication Therapy". Antibiotics 9, nr 10 (26.09.2020): 645. http://dx.doi.org/10.3390/antibiotics9100645.
Pełny tekst źródłaStreszczenie:
Background: Helicobacter pylori eradication containing the potassium-competitive acid blocker, vonoprazan, achieves a higher eradication rate than therapy with proton pump inhibitors (PPIs). Because vonoprazan is mainly metabolized by CYP3A4/5, CYP genotype may affect the eradication rate. We investigated the influence of antibiotic susceptibility and CYP3A4/5 and CYP2C19 genotypes on the eradication rates. Methods: A total of 307 Japanese who were genotyped for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17, and investigated for susceptibility to antimicrobial agents, received vonoprazan-containing regimens: (1) With amoxicillin and clarithromycin as the first-line treatment; (2) with amoxicillin and metronidazole as the second-line treatment; or (3) with amoxicillin and sitafloxacin as the third-line treatment. Results: The eradication rate was 84.5% (95% confidence interval [CI]: 78.9–89.1%) using first-line, 92.6% (95% CI: 82.1–97.9%) using second-line and 87.5% (95% CI: 73.1–95.8%) using third-line treatment. Infection with clarithromycin-resistant strains was a predictive factor for failed eradication (odds ratio: 5.788, 95% CI: 1.916–17.485, p = 0.002) in multivariate analysis. No significant differences were observed in the eradication rate of regimens among CYP3A4, CYP3A5 and CYP2C19 genotypes. Conclusions: Genotyping for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17 before vonoprazan-containing eradication treatment may not be useful for predicting clinical outcomes.
49
Yang, Liang, Yuguang Wang, Huanhua Xu, Guangyao Huang, Zhaoyan Zhang, Zengchun Ma i Yue Gao. "Panax ginseng Inhibits Metabolism of Diester Alkaloids by Downregulating CYP3A4 Enzyme Activity via the Pregnane X Receptor". Evidence-Based Complementary and Alternative Medicine 2019 (21.03.2019): 1–13. http://dx.doi.org/10.1155/2019/3508658.
Pełny tekst źródłaStreszczenie:
To investigate the effects of P. ginseng C.A. Mey (P. ginseng) on the metabolism of diester alkaloids and explore the potential mechanism. P. ginseng was administered orally to rats for 7 days, after which liver microsome samples were prepared and then incubated with diester alkaloids. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to determinate the concentration of diester alkaloids to calculate the clearance rate. The cocktail method was used to evaluate the effects of oral administration of P. ginseng extracts on the activities of cytochrome P450 (CYP) isoforms in rats through the changes in the pharmacokinetic parameters of the probe drugs. The protein and gene expression of CYP3A2 and pregnane X receptor (PXR) in rats were evaluated by western blotting and quantitative PCR. The specific enzyme inhibitor method and human recombinant enzyme method were used to identify the involvement of sub-CYPs in the metabolism of diester alkaloids in human liver microsomes (HLMs). The clearances of aconitine, mesaconitine, and hypaconitine in the P. ginseng groups were lower than those of the control group. The areas under the curve of midazolam were 2.37 ± 1.05, 4.96 ± 0.51, and 6.23 ± 1.30 mg·L−1·h for the low-, medium-, and high-dose P. ginseng groups, respectively, which were higher than that of the control (2.23 ± 0.64 mg·L−1·h). The clearances of midazolam for the medium- (1.87 ± 0.16 L·h−1·kg−1) and high-dose (1.60 ± 0.34 L·h−1·kg−1) P. ginseng groups were lower than that of the control group (4.66 ± 1.43 L·h−1·kg−1). After exposure to P. ginseng extracts, the gene and protein expression levels of CYP3A4 and PXR were decreased. The hepatic metabolism rates of aconitine, mesaconitine, and hypaconitine in HLMs were decreased to 60.37%, 21.67%, and 10.11%, respectively, when incubated with ketoconazole, a specific inhibitor for CYP3A. The kinetic plots indicated that the KM and Vmax values of CYP3A4 were 10.08 ± 3.26 μM and 0.12 ± 0.01nmol·mg protein−1·min−1 for aconitine, 131.3 ± 99.75 μM and 0.73 ± 0.44 nmol·mg protein−1·min−1 for mesaconitine, and 17.05 ± 9.70 μM and 0.16 ± 0.04 nmol·mg protein−1·min−1 for hypaconitine, respectively. The in vitro mean intrinsic clearance rates by CYP3A4 were 0.0119, 0.0056, and 0.0091 mL·nmol CYP−1·min−1 for aconitine, mesaconitine, and hypaconitine, respectively. Therefore we implied that P. ginseng inhibited the metabolism of diester alkaloids in vitro and decreased the CYP3A4 enzyme activity as well as the gene and protein expression of CYP3A4 and PXR in vivo. CYP3A4 had a larger effect on diester alkaloid metabolism than the other human CYP isoforms, CYP1A2, CYP2C9, and CYP2E1.
50
Oda, Yutaka, Katsuji Furuichi, Kazuo Tanaka, Toyoko Hiroi, Susumu Imaoka, Akira Asada, Mitsugu Fujimori i Yoshihiko Funae. "Metabolism of a New Local Anesthetic, Ropivacaine, by Human Hepatic Cytochrome P450". Anesthesiology 82, nr 1 (1.01.1995): 214–20. http://dx.doi.org/10.1097/00000542-199501000-00026.
Pełny tekst źródłaStreszczenie:
Background Ropivacaine is a local anesthetic with a long duration of action. Although it is less toxic than bupivacaine, local anesthetic toxicity is possible when the plasma concentration is increased. Because ropivacaine is an amide-type local anesthetic, it is metabolized by cytochrome P450 (P450) in the liver, and its elimination and plasma concentration can be dependent on the level of P450. The purpose of this investigation was to elucidate the metabolism of ropivacaine by human hepatic P450. Methods The metabolism of ropivacaine was compared using recombinant human and purified rat hepatic P450 isozymes. An inhibition study using antibodies against rat P450 was performed using hepatic microsomes from human and rat to identify which P450s are involved in ropivacaine metabolism. Results Ropivacaine was metabolized to 2',6'-pipecoloxylidide (PPX), 3'-hydroxyropivacaine (3'-OH Rop), and 4'-hydroxyropivacaine (4'-OH Rop) by hepatic microsomes from human and rat. PPX was a major metabolite of both human and rat hepatic microsomes. In a reconstituted system with rat P450. PPX was produced by CYP2C11 and 3A2, 4'-OH Rop by CYP1A2, and 3'-OH Rop by CYP1A2 and 2D1. Formation of PPX in rat hepatic microsomes was inhibited by anti CYP3A2, but not by CYP2C11 antibody, and formation of 3'-OH Rop was inhibited by CYP1A2 and 2D1 antibodies. Anti CYP3A2 and 1A2 antibodies inhibited the formation of PPX and 3'-OH Rop in human hepatic microsomes, respectively. Recombinant human P450s expressed in lymphoblast cells were used for further study. CYP3A4 and 1A2 formed the most PPX and 3'-OH Rop, respectively. Ropivacaine N-dealkylation and 3'-hydroxylation activities correlated well with the level of CYP3A4 and 1A2 in human hepatic microsomes, respectively. Conclusions Ropivacaine was metabolized to PPX, 3'-OH Rop, and 4'-OH Rop by hepatic P450. PPX was a major metabolite in human hepatic microsomes. CYP3A4 was involved in producing PPX. CYP1A2 was involved in the formation of 3'-OH Rop in human hepatic microsomes.