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Автор: Grafiati
Опубліковано: 14 березня 2023

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1

Varatharajan, Savitha, Ajay Abraham, Shaji R. Velayudhan, Rayaz Ahmed, Aby Abraham, Biju George, Mammen Chandy, Alok Srivastava, Vikram Mathews, and Poonkuzhali Balasubramanian. "Carbonyl Reductase 1 Expression and Polymorphisms Influence Daunorubicin Metabolism in AML." Blood 118, no. 21 (November 18, 2011): 2484. http://dx.doi.org/10.1182/blood.v118.21.2484.2484.

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Abstract Abstract 2484 Treatment failure in AML can be attributed to resistance to chemotherapeutic drugs. Induction chemotherapy of AML involves combination of Daunorubicin (Dnr) and Cytarabine. Up-regulation in the expression of efflux transporters such as ABCB1 and ABCG2 has been shown to be one of the causes of Dnr resistance in AML. Apart from efflux transporters, increased expression of the Dnr metabolising enzymes (Carbonyl reductase 1 (CBR1) and CBR3) also can influence the cytotoxic activity of Dnr against leukemic cells. Aim of the present study is to investigate: i) the role of mRNA expression of Dnr metabolising enzymes (CBR1 and CBR3) on the in vitro cytotoxicity of Dnr in primary AML cells and ii) effect of Single nucleotide polymorphisms (SNPs) in CBR1 and CBR3 on the plasma pharmacokinetics of Dnr and Daunorubicinol (DOL) in AML patients. Ninety patients with AML (excluding AML-M3) at diagnosis before the initiation of therapy were included. Bone marrow (BM) was collected at diagnosis and blast percentage in our cohort of patients ranged from 20–100%. Mononuclear cells (MNCs) were isolated by density gradient centrifugation. Total RNA was extracted from BMMNCs and cDNA was prepared. CBR1 and CBR3 mRNA expression was measured using Taqman based quantitative RT-PCR normalized to GAPDH. In-vitro cytotoxicity of Dnr was determined by MTT cell viability assay. Intracellular levels of Dnr and DOL was estimated by HPLC coupled with Fluorescence detector (FD). SNPs in CBR1 and CBR3 were screened by PCR followed by sequencing. In addition, plasma samples during Dnr infusion was collected at 0, 1, 2, 4, 6 and 24hrs from 24 of the 90 AML patients. Levels of Dnr and DOL in the plasma samples were estimated by HPLC coupled with FD and Area under Curve (AUC) for Dnr and DOL were calculated. CBR1 (range: 0.02–253.15) and CBR3 (range: 8.24– 29296.67) mRNA expression showed wide inter-individual variation. Intracellular levels of Dnr (range: 17.98–1718ng/3×106cells) and DOL (range: 2.76–62.07ng/3×106cells) showed 95 and 22 fold variation respectively. IC50 of Dnr in these samples ranged from 0.05 to 3.15 μM. Based on the IC50, samples were categorized as sensitive (IC50<0.5μM), intermediate (IC50: 0.5–1.0μM) and resistant (IC50>1.0μM) to Dnr. CBR1 expression was significantly higher in resistant samples (median-102.99: range: 7.18–253.15) compared to intermediate (median- 29.73: range: 0.02–224.23) and sensitive samples (median-18.67: range: 0.34–105.40 p=0.0154) [Figure 1]. In addition, significant correlation between CBR1 expression and intracellular DOL levels was observed (r= 0.52; p<0.0001), as samples with higher CBR1 expression had increased DOL levels. CBR3 expression did not show any significant association with invitro cytotoxicity or intracellular DOL levels. Five SNPs in CBR1 and 3 in CBR3 were identified. CBR1 SNPs, rs20572, rs9024 and rs25678 were in complete linkage disequilibrium (LD). Variant of rs25678 and rs20572/rs9024 had an allelic frequency of 0.244 and 0.20 respectively. Among CBR3 SNPs, variants of two non-synonymous polymorphisms rs8133502 and rs1056892 showed allelic frequency of 0.31 and 0.51 respectively. AUC of Dnr and DOL in plasma samples ranged from 22–2474ng*h/ml and 37–2027 ng*h/ml respectively while clearance of Dnr ranged from 0.04 to 3.34 L/h. Plasma DOL AUC, unlike in vitro intracellular DOL, did not show any significant association with CBR1 and CBR3 expression. In patients with variant rs25678 genotype, Dnr AUC was higher and clearance was lower compared to the wild type genotype, reaching a trend to statistical significance (p=0.0537 and 0.1184 for Dnr AUC and clearance). Influence of Dnr and DOL plasma levels on clinical outcome, if any, remains to be evaluated. This is the first report showing the influence of CBR1 and CBR3 in in-vitro cytotoxicity of Dnr and role of SNPs in CBR1 and CBR3 in plasma pharmacokinetics of Dnr in AML patients. To conclude, higher expression of CBR1 confers resistance to Dnr in primary AML cells and polymorphisms of this gene may influence the pharmacokinetics of Dnr. Disclosures: No relevant conflicts of interest to declare.
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2

Blanco, Javier G., Can-Lan Sun, Wendy Landier, Lu Chen, Diego Esparza-Duran, Wendy Leisenring, Allison Mays, et al. "Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group." Journal of Clinical Oncology 30, no. 13 (May 1, 2012): 1415–21. http://dx.doi.org/10.1200/jco.2011.34.8987.

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Purpose Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and Methods One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. Results A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Conclusion This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
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3

Hu, Dawei, Namiki Miyagi, Yuki Arai, Hiroaki Oguri, Takeshi Miura, Toru Nishinaka, Tomoyuki Terada, et al. "Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1." Organic & Biomolecular Chemistry 13, no. 27 (2015): 7487–99. http://dx.doi.org/10.1039/c5ob00847f.

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Анотація:
Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs.
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4

Vyskočilová, Erika, Barbora Szotáková, Lenka Skálová, Hana Bártíková, Jitka Hlaváčová, and Iva Boušová. "Age-Related Changes in Hepatic Activity and Expression of Detoxification Enzymes in Male Rats." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/408573.

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Process of aging is accompanied by changes in the biotransformation of xenobiotics and impairment of normal cellular functions by free radicals. Therefore, this study was designed to determine age-related differences in the activities and/or expressions of selected drug-metabolizing and antioxidant enzymes in young and old rats. Specific activities of 8 drug-metabolizing enzymes and 4 antioxidant enzymes were assessed in hepatic subcellular fractions of 6-week-old and 21-month-old male Wistar rats. Protein expressions of carbonyl reductase 1 (CBR1) and glutathioneS-transferase (GST) were determined using immunoblotting. Remarkable age-related decrease in specific activities of CYP2B, CYP3A, and UDP-glucuronosyl transferase was observed, whereas no changes in activities of CYP1A2, flavine monooxygenase, aldo-keto reductase 1C, and antioxidant enzymes with advancing age were found. On the other hand, specific activity of CBR1 and GST was 2.4 folds and 5.6 folds higher in the senescent rats compared with the young ones, respectively. Interindividual variability in CBR1 activity increased significantly with rising age. We suppose that elevated activities of GST and CBR1 may protect senescent rats against xenobiotic as well as eobiotic electrophiles and reactive carbonyls, but they may alter metabolism of drugs, which are CBR1 and especially GSTs substrates.
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5

Bell, Rachel, Elisa Villalobos, Mark Nixon, Allende Miguelez-Crespo, Matthew Sharp, Martha Koerner, Emma Allan, et al. "Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A806. http://dx.doi.org/10.1210/jendso/bvab048.1639.

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Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.
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6

Waclawik, Agnieszka, and Adam J. Ziecik. "Differential expression of prostaglandin (PG) synthesis enzymes in conceptus during peri-implantation period and endometrial expression of carbonyl reductase/PG 9-ketoreductase in the pig." Journal of Endocrinology 194, no. 3 (September 2007): 499–510. http://dx.doi.org/10.1677/joe-07-0155.

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Prostaglandins (PGs) play a pivotal role in luteolysis, maternal recognition of pregnancy, and implantation. In many species, including pigs, both conceptus (embryo and associated membranes) and endometrium synthesize PGE2, which may antagonize PGF2α by playing a luteotropic/antiluteolytic role. Previously, we have reported expression profiles of PG G/H synthases (PGHS-1 and PGHS-2), PGE synthase (mPGES-1), and PGF synthase (PGFS) in the endometrium of cyclic and pregnant pigs. In the present study, expression of above-mentioned PG synthesis enzymes and PG 9-ketoreductase (CBR1), which converts PGE2 into PGF2α, and the PGE2/PGF2α ratios were investigated in porcine peri- and post-implantation conceptuses. Furthermore, expression of CBR1 was examined in the endometrium. PGHS-2 and mPGES-1 were upregulated, and PGHS-1, PGFS, and CBR1 were downregulated in conceptuses during trophoblastic elongation. A second increase of mPGES-1 mRNA occurred after days 20–21 of pregnancy. After initiation of implantation, expression of PGHS-1, PGFS, and CBR1 in conceptuses increased and remained higher until days 24–25 of pregnancy. Comparison of the endometrial CBR1 protein expression in cyclic and pregnant gilts revealed upregulation on days 16–17 of the cycle and downregulation on days 10–11 of pregnancy. In conclusion, reciprocal expression of PGHS-2, mPGES-1, PGFS, and CBR1 in day 10–13 conceptuses and decrease of endometrial CBR1 may be important in increasing the PGE2/PGF2α ratio during maternal recognition of pregnancy. This study indicates that PGE2 produced via PGHS-2 and mPGES-1 in conceptus may be involved in corpus luteum control. Moreover, high expression of conceptus PGHS-1, mPGES-1, PGFS, and CBR1 after initiation of implantation suggests their significant role in placentation.
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7

Guo, Chunming, Wangsheng Wang, Chao Liu, Leslie Myatt та Kang Sun. "Induction of PGF2α Synthesis by Cortisol Through GR Dependent Induction of CBR1 in Human Amnion Fibroblasts". Endocrinology 155, № 8 (1 серпня 2014): 3017–24. http://dx.doi.org/10.1210/en.2013-1848.

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Abundant evidence indicates a pivotal role of prostaglandin F2α (PGF2α) in human parturition. Both the fetal and maternal sides of the fetal membranes synthesize PGF2α. In addition to the synthesis of PGF2α from PGH2 by PGF synthase (PGFS), PGF2α can also be converted from PGE2 by carbonyl reductase 1 (CBR1). Here, we showed that there was concurrent increased production of cortisol and PGF2α in association with the elevation of CBR1 in human amnion obtained at term with labor versus term without labor. In cultured primary human amnion fibroblasts, cortisol (0.01–1μM) increased PGF2α production in a concentration-dependent manner, in parallel with elevation of CBR1 levels. Either siRNA-mediated knockdown of glucocorticoid receptor (GR) expression or GR antagonist RU486 attenuated the induction of CBR1 by cortisol. Chromatin immunoprecipitation (ChIP) showed an increased enrichment of both GR and RNA polymerase II to CBR1 promoter. Knockdown of CBR1 expression with siRNA or inhibition of CBR1 activity with rutin decreased both basal and cortisol-stimulated PGF2α production in human amnion fibroblasts. In conclusion, CBR1 may play a critical role in PGF2α synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via GR-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.
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8

Ferguson, Daniel C., Qiuying Cheng, and Javier G. Blanco. "Characterization of the Canine Anthracycline-Metabolizing Enzyme Carbonyl Reductase 1 (cbr1) and the Functional Isoform cbr1 V218." Drug Metabolism and Disposition 43, no. 7 (April 27, 2015): 922–27. http://dx.doi.org/10.1124/dmd.115.064295.

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9

Madadi Mahani, Nosrat, Alireaza Mohadesi Zarandi, and Azra Horzadeh. "QSAR studies of novel iminochromene derivatives as as carbonyl reductase 1 (CBR1) inhibito." Marmara Pharmaceutical Journal 22, no. 2 (April 6, 2018): 227–36. http://dx.doi.org/10.12991/mpj.2018.60.

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10

Miura, Takeshi, Ayako Taketomi, Toru Nishinaka, and Tomoyuki Terada. "Regulation of human carbonyl reductase 1 (CBR1, SDR21C1) gene by transcription factor Nrf2." Chemico-Biological Interactions 202, no. 1-3 (February 2013): 126–35. http://dx.doi.org/10.1016/j.cbi.2012.11.023.

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11

Arai, Yuki, Satoshi Endo, Namiki Miyagi, Naohito Abe, Takeshi Miura, Toru Nishinaka, Tomoyuki Terada, et al. "Structure–activity relationship of flavonoids as potent inhibitors of carbonyl reductase 1 (CBR1)." Fitoterapia 101 (March 2015): 51–56. http://dx.doi.org/10.1016/j.fitote.2014.12.010.

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12

Gonzalez-Covarrubias, Vanessa, Jianping Zhang, James L. Kalabus, Mary V. Relling, and Javier G. Blanco. "Pharmacogenetics of Human Carbonyl Reductase 1 (CBR1) in Livers from Black and White Donors." Drug Metabolism and Disposition 37, no. 2 (November 20, 2008): 400–407. http://dx.doi.org/10.1124/dmd.108.024547.

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13

Jang, Miran, and Sung Soo Kim. "Inhibition of Carbonyl Reductase 1(CBR1) Enhances Arsenic Trioxide-mediated Apoptosis in Leukemia Cells." Free Radical Biology and Medicine 49 (January 2010): S63. http://dx.doi.org/10.1016/j.freeradbiomed.2010.10.148.

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14

Quiñones-Lombraña, Adolfo, Qiuying Cheng, Daniel C. Ferguson, and Javier G. Blanco. "Transcriptional regulation of the canine carbonyl reductase 1 gene ( cbr1 ) by the specificity protein 1 (Sp1)." Gene 592, no. 1 (October 2016): 209–14. http://dx.doi.org/10.1016/j.gene.2016.08.005.

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15

Gonzalez-Covarrubias, Vanessa, James L. Kalabus, and Javier G. Blanco. "Inhibition of Polymorphic Human Carbonyl Reductase 1 (CBR1) by the Cardioprotectant Flavonoid 7-monohydroxyethyl Rutoside (monoHER)." Pharmaceutical Research 25, no. 7 (May 1, 2008): 1730–34. http://dx.doi.org/10.1007/s11095-008-9592-5.

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16

Cheng, Q., C. Sanborn, D. Ferguson, and J. G. Blanco. "Short Communication DNA sequence variants in the carbonyl reductase 1 (cbr1) gene in seven breeds of Canis lupus familiaris." Genetics and Molecular Research 11, no. 2 (2012): 1109–16. http://dx.doi.org/10.4238/2012.april.27.10.

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17

Gonzalez-Covarrubias, Vanessa, Debashis Ghosh, Sukhwinder S. Lakhman, Lakshmi Pendyala, and Javier G. Blanco. "A Functional Genetic Polymorphism on Human Carbonyl Reductase 1 (CBR1 V88I) Impacts on Catalytic Activity and NADPH Binding Affinity." Drug Metabolism and Disposition 35, no. 6 (March 7, 2007): 973–80. http://dx.doi.org/10.1124/dmd.107.014779.

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18

Kalabus, James L., Qiuying Cheng, and Javier G. Blanco. "MicroRNAs Differentially Regulate Carbonyl Reductase 1 (CBR1) Gene Expression Dependent on the Allele Status of the Common Polymorphic Variant rs9024." PLoS ONE 7, no. 11 (November 1, 2012): e48622. http://dx.doi.org/10.1371/journal.pone.0048622.

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19

Lakhman, Sukhwinder S., Xiaomin Chen, Vanessa Gonzalez-Covarrubias, Erin G. Schuetz, and Javier G. Blanco. "Functional Characterization of the Promoter of Human Carbonyl Reductase 1 (CBR1). Role of XRE Elements in Mediating the Induction of CBR1 by Ligands of the Aryl Hydrocarbon Receptor." Molecular Pharmacology 72, no. 3 (June 14, 2007): 734–43. http://dx.doi.org/10.1124/mol.107.035550.

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20

Seliger, Jan Moritz, Hans-Jörg Martin, Edmund Maser, and Jan Hintzpeter. "Potent inhibition of human carbonyl reductase 1 (CBR1) by the prenylated chalconoid xanthohumol and its related prenylflavonoids isoxanthohumol and 8-prenylnaringenin." Chemico-Biological Interactions 305 (May 2019): 156–62. http://dx.doi.org/10.1016/j.cbi.2019.02.031.

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21

Jordheim, Lars-Petter, Vincent Ribrag, Herve Ghesquieres, Sophie Pallardy, Richard Delarue, Herve Tilly, Corinne Haioun, Fabrice Jardin, Gilles Salles, and Charles Dumontet. "Single Nucleotide Polymorphisms in ABCB1 and CBR1 Predict Toxicity to R-CHOP Type Regimens in Patients with Diffuse Non Hodgkin's Lymphoma." Blood 120, no. 21 (November 16, 2012): 1616. http://dx.doi.org/10.1182/blood.v120.21.1616.1616.

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Abstract Abstract 1616 We analyzed single nucleotide polymorphisms (SNPs) in patients with diffuse large B-cell lymphoma treated in the prospective GELA LNH 2003 studies. Peripheral blood DNA samples collected at diagnosis before chemotherapy were obtained from 760 patients (among a total of 1367 accrued) including 441 randomized to received R-CHOP or modified R-CHOP (LNH 03–7B) and 319 who received R-ACVBP. The median age was 59 years (range 18–93) and there were 441 males and 319 females. 429 were IPI 0–2 (56.4%) and 331 were IPI 3–5 (43.6%). 119 patients had an ECOG performance status >1 (15.7%). B symptoms were present in 261 cases (34.4%). Serum albumin was below 35 g/L in 190 patients (27.7%). 489 patients (66.9%) had complete or unconfirmed complete response after induction therapy and 167 (22%) had partial response. At 5 years the overall survival was 73.9% (95% C.I. 69.7–77.6) and the progression free survival was 64.4% (95% CI 60.1–68.4). A total of 17 SNPs in 13 genes involved in drug metabolism or apopotosis were genotyped by TaqMan SNP Genotyping Assays (Applied Biosystems) on a LC480 (Roche) and correlated with toxicity occurring during treatment. Toxicity was evaluated prospectively using the NCI CTC V3 scale and associations were determined between specific genotypes and grade 3 or 4 toxicities. The studied genes were ABCB1, CAT, CBR1, FGFR4, IL10, NRG1, SLC22A16, SOD2, UGT1A1, CYP3A4, GSTP1, GSTM1 and GSTT1. Among these, 4 SNPs located in ABCB1 and CBR1 were found to be significantly associated with treatment-induced toxicity. The two SNPs localized in the ABCB1 gene were rs2032582 which was correlated with thrombocytopenia (p=0.04) and rs2229109 which was correlated with vomiting (p=0.003) and diarrhoea (p=0.007). The two SNPs localized in the CBR1 gene were rs20572 and rs9024 which were both correlated with anemia, thrombocytopenia and diarrhoea (p=0.02). ABCB1 codes for the drug efflux pump Pgp which has mainly been evaluated for its role in chemoresistance, is also known to be a key regulator of drug elimination and a determinant of pharmacokinetics. CBR1 codes for carbonyl reductase 1 which is involved in the first step of the metabolism of doxorubicin. These results suggest that genotyping of peripheral blood cells could help predict severe toxicity in patients receiving R-CHOP type regimens. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.
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22

Kalabus, James L., Qiuying Cheng, Raqeeb G. Jamil, Erin G. Schuetz, and Javier G. Blanco. "Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene." Toxicology Letters 211, no. 3 (June 2012): 266–73. http://dx.doi.org/10.1016/j.toxlet.2012.04.006.

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23

Docherty, Anna R., Arden Moscati, Tim B. Bigdeli, Alexis C. Edwards, Roseann E. Peterson, Daniel E. Adkins, John S. Anderson, Jonathan Flint, Kenneth S. Kendler, and Silviu-Alin Bacanu. "Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE." Psychological Medicine 50, no. 5 (April 2, 2019): 793–98. http://dx.doi.org/10.1017/s0033291719000618.

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AbstractBackgroundThe Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets.MethodsUsing a large case–control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status.ResultsOver and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD.ConclusionsResults indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.
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24

Fan, L., J. Y. Guo, C. I. Wong, R. Lim, H. L. Yap, Y. M. Khoo, P. Iau, B. C. Goh, H. S. Lee, and S. C. Lee. "Genetic variants in human carbonyl reductase 3 (CBR3) and their influence on doxorubicin pharmacokinetics in Asian breast cancer patients." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2505. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2505.

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2505 Background: Human carbonyl reductase 3 (CBR3) is one of the main metabolizing enzymes to extensively reduce doxorubicin to its major active metabolite, doxorubicinol in normal and tumor tissues. Recently, the CBR3 958G>A (V244M) genetic variant has been described to alter function in vitro. We postulate that CBR3 genetic variants could contribute to the inter-individual variability of doxorubicin pharmacokinetics in breast cancer patients. Methods: We studied 101 female breast cancer patients (66 Chinese, 26 Malay, 7 Indian and 2 of other ethnic origins) who were treated with doxorubicin at 75mg/m2 every 3 weeks. Comprehensive sequencing of the 3 exons of CBR3, including the splice-site junctions was performed. Plasma concentrations of doxorubicin and doxorubicinol were analyzed during the first doxorubicin cycle. Results: Five CBR3 coding region variants (239G>A, 483C>T, 507C>T, 598G>A and 958G>A) were detected, of which 239G>A, 598G>A and 958G>A were non-synonymous. 598G>A was novel, and was found in 1 Malay patient who was heterozygous. The genotype distributions of 239G>A and 958G>A were 36%/30%/34%, and 40%/36%/24% respectively for GG/AG/AA. The 239GG variant was associated with significantly higher AUC of doxorubicinol and AUC ratio of doxorubicinol to doxorubicin than the AG and AA variants (AUC of doxorubicinol 2.18±1.37ug/ml*h (GG) vs 2.04±2.11ug/ml*h (AG), p=0.05, and 1.55±0.61ug/ml*h (AA), p=0.004; AUC ratio of doxorubicinol to doxorubicin 1.90±1.29 (GG) vs 1.72±1.34 (AG), p=0.025, and 1.45±0.67 (AA), p=0.006). Patients with the 958AA variant had significantly higher AUC of doxorubicinol than those with the 958GG variant (2.29±1.60ug/ml*h vs 1.56±0.60ug/ml*h, p=0.009). The 239GG variant was more common in our population than in Caucasians (36% vs 20%. p=0.027), while the 958AA variant was more common than reported in Caucasians (24% vs 8%, p=0.014) and Japanese (24% vs 7%, p=0.016). Conclusions: CBR3 genetic variants may influence the pharmacokinetics of doxorubicin and its major metabolite doxorubicinol. Inter-ethnic differences in frequencies of CBR3 genetic variants exist and may account for differences in pharmacokinetics and pharmacodynamics of doxorubicin between different populations. No significant financial relationships to disclose.
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25

Santana, Sanzio, Thassila Nogueira Pitanga, Jeanne Machado de Santana, Dalila Lucíola Zanette, Corynne Stephanie A. Adanho, Nívea Farias Luz, Valéria Matos Borges, and Marilda Souza Goncalves. "Hydroxyurea Exhibits Antioxidant Activity Via the Nrf2 Pathway- Antioxidant/Electrophile Response Element Regulated By p62/ SQSTM1." Blood 132, Supplement 1 (November 29, 2018): 3648. http://dx.doi.org/10.1182/blood-2018-99-117220.

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Abstract Introduction: The pathophysiology of sickle cell anemia (HF) is characterized by hemolytic and intermittent vasoconstrictive events with increased redox status in the vascular microenvironment that favors the chronic inflammation. Objectives: To investigate whether hydroxyurea (HU) acts in the inhibition/minimization of reactive oxygen/nitrogen species (ROS/RNS) and in the modulation of in vitro the antioxidant genes expression. Methods: DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assay was performed to determine the antioxidant activity of HU using L-ascorbate (L-Asc) and butylated hydroxytoluene (BHT) as antioxidant controls. Human umbilical vein endothelial cell (HUVEC) and peripheral blood mononuclear cells (PBMC) were challenged with HU in the presence or absence of hemin for evaluation the cytotoxicity, inhibition of superoxide anions, nitrate/nitrite production and expression of antioxidant enzymes SOD1 (superoxide dismutase-1); GPx (glutathione peroxidase); GSR (glutathione-disulfide reductase); and HMOX1 (heme oxygenase-1 by RT-qPCR. Microarray analyses were performed on HUVEC stimulated with HU. Results: HU showed scavenging activity (similar to BHT) at concentrations equivalent to that found in the plasma of patients taking the drug (~200 μM). Treatments with HU alone or in combination with hemin did not induce toxicity in PBMC and HUVEC. HU decreases the accumulation of superoxide anions in PBMC in the presence or absence of hemin and the combined treatment of HU with hemin stimulated nitrate/nitrite production in PBMC. HU increases expression of SOD1 and GPx in PBMC and HUVEC. The increase in GSR expression was observed in PBMC and HUVEC submitted to the combined treatment of HU with hemin. HU did not induce HMOX1 expression and did not decrease its expression in combination with hemin in both, PBMC and HUVEC (Figure 1). The microarray assay showed that HU induces the expression of cellular antioxidant components, such as SOD2, GSR, GST1 (glutathione S-transferase-1, GSTM2 (glutathione S-transferase mu 2), MGST1 (microsomal glutathione S-transferase 1), CBR1 (carbonyl reductase 1), protein kinases phosphatidylinositol 3-phosphate C (PRKCB, PRKCZ, PIK3C2B) and p62/SQSTM1 (sequestosome 1) (Table 1). In contrast, a decrease in BACH1 (BTB domain and CNC homolog 1) transcriptional factor expression was observed. Upstream analysis demonstrated prediction of activation for the transcriptional factor JUN and miR-155-5p. Conclusion: The findings indicate that HU can act (i) directly inhibiting on the direct inhibition of ROS/RNS; (ii) inducing nitrite/nitrate production in the presence of hemin; (iii) besides stimulating the antioxidant cellular response by inducing the antioxidant/electrophile response element (ARE/EpRE) mediated by Nrf2 under p62/SQSTM1 regulation. Disclosures No relevant conflicts of interest to declare.
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Budik, S., I. Walter, R. Ertl, and C. Aurich. "Detection of Carbonyl Reductase-1 (CBR-1) enzyme in pre-implantation equine conceptuses and its putative role in embryo mobility." Journal of Equine Veterinary Science 89 (June 2020): 103065. http://dx.doi.org/10.1016/j.jevs.2020.103065.

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Zhou, Yumin, Man Wang, Weiyan Yang, Jianjun Li, Jialin Li, Yueying Hu, Wei Wang, Chunli Che, and Hong Qi. "Environmental and Genetic Factors in the Pathogenesis of COPD in the Road-Working Population." Disease Markers 2021 (April 29, 2021): 1–10. http://dx.doi.org/10.1155/2021/9953234.

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Background. Chronic obstructive pulmonary disease (COPD) is a typical heterogeneous condition caused by environmental and genetic risk factors. Objectives. We investigated extrinsic (environmental) and intrinsic (genetic) factors contributing to the development of COPD in a nonsmoker road-working population in Northeast China. Method. The target population was divided into a COPD group and an exposed control group. Another healthy nonroad working nonsmoker control group was also included for environmental factor comparison. Peripheral blood was collected and analyzed using inductively coupled plasma mass spectrometry for inorganic elements of PM2.5, and microarray, rt-PCR, and Multiplex ELISA for genetic factors. Results. Forty-three COPD road workers, thirty-nine non-COPD road workers, and 52 age and gender-matched healthy nonroad workers were enrolled. There were significantly higher levels in all 24 inorganic elements in the COPD group compared with the healthy control group except potassium and manganese, while the majority of inorganic elements were similar between the COPD group and the exposed control group except in aluminum and cobalt. There were 39 genes showing significant differences between the COPD group and the exposed control group. Collagen, type XV, alpha 1 (COL15A1), Meis homeobox 1 (MEIS1), carbonyl reductase 3 (CBR3), and amine oxidase, copper containing 3 (AOC3) were confirmed by rt-PCR to be differentially expressed. Their correlations with blood cytokines were also evaluated. Conclusions. Aluminum might contribute to the development of COPD in the road-working population. CBR3 and AOC3 seem expressed in different patterns than previously reported, evidenced by their correlation with proinflammatory and anti-inflammatory cytokines.
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28

Gaudy, Allison, Gerald J. Fetterly, Alex A. Adjei, Tracey L. O'Connor, Adolfo Quinones, Javier G. Blanco, Daniel Ferguson, Patricia D. Meholick, and James Kalabus. "Investigation of the pharmacogenetic influences of carbonyl reductase on doxorubicin and doxorubicinol in breast cancer patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2594. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2594.

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2594 Background: The anthracycline doxorubicin (DOX) is widely used to treat breast cancer. Doxorubicin is associated with pharmacokinetic and pharmacodynamic variability and despite its use for several years there is limited understanding behind it. Hepatic carbonyl reductases (CBR1 and CBR3) catalyze the reduction of DOX into its main circulating C-13 metabolite doxorubicinol (DOXOL). Polymorphisms in CBR1 and CBR3 influence synthesis of DOXOL, and could potentially play a role in the pharmacokinetic (PK) variability seen with doxorubicin treatment. In this study, we examined the influence of genetic polymorphisms in CBR1 and CBR3 on DOX and DOXOL PK. Methods: DOX was administered IV to 79 breast cancer patients at 60 mg/m2. Population PK modeling was performed on the parent concentration-time profiles with the following patient factors: [BSA (1.4-2.6 m2), weight (40-140 kg), age (25-75), race (78% white), CBR1 rs9024 (78% wild-type), CBR3 V244M (47% wild-type), CBR3 C4Y (20.5% wild-type); followed by model validation. Noncompartmental analysis (NCA) was performed for both DOX and DOXOL and the metabolic ratio was calculated as AUCDOXOL0-24:AUCDOX0-24. Results: A two-compartment model was used to describe DOX PK. Mean predicted (%SEM) clearance (CL), plasma volume (Vp), tissue volume and distribution clearance were 28.1 L/hr (7.72), 22.5 L (3.80), 257 L (13.8) and 13.6L (21.8), respectively. Interpatient variability on CL and Vp were 22.1% and 12.6%, respectively. BSA was found to be a significant predictor of the interpatient variability on CL. No other patient factors were found to be significant on parent drug PK. The metabolic ratio, assessing the conversion of DOX to DOXOL, was stratified by different polymorphisms of CBR1 and CBR3. There were no significant differences in metabolic ratio due to CBR1 and CBR3 genotypes. Conclusions: A PK model was developed that was able to characterize DOX pharmacokinetics. CBR1 and CBR3 polymorphisms were tested as covariates but were not found to be significant contributors to the variable pharmacokinetic profiles of DOX and DOXOL.
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Elsayed, Abdelrahman H., Huiyun Wu, Xueyuan Cao, Susana C. Raimondi, James R. Downing, Raul Ribeiro, Tanja A. Gruber, et al. "A 5-Gene Ara-C, Daunorubicin and Etoposide (ADE) Drug Response Score As a Prognostic Tool to Predict AML Treatment Outcome." Blood 134, Supplement_1 (November 13, 2019): 1429. http://dx.doi.org/10.1182/blood-2019-128787.

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Introduction: Cytarabine, daunorubicin and etoposide (ADE) are commonly used for remission and intensification of pediatric acute myeloid leukemia (AML). However, development of drug resistance is a major cause of treatment failure. In this study, we performed a comprehensive evaluation of expression levels of genes of pharmacological significance (pharmacokinetic /pharmacodynamic) to ADE and derived a drug response score predictive of treatment outcomes in pediatric AML patients. Methods: This study included 163 cases (median age=8.79 year, range= (0.013-21.1)) with AML enrolled in the multicenter AML02 clinical trial (ClinicalTrials.gov Identifier: NCT00136084) with Affymetrix U133A microarray gene expression and clinical data available. We used a penalized LASSO regression algorithm (glmnet R-package) to fit a cox regression model on diagnostic leukemic cell gene expression levels of 66 genes of pharmacological significance to ADE. We performed 1000 bootstraps of LASSO regression with event free survival (EFS) as the outcome variable and the five genes represented in at least 95% of the models were included to build an ADE-Response Score (ADE-RS) equation. Patients were classified into low or high score groups using recursive portioning implemented in Rpart-R package and evaluated for association with minimal residual disease after induction I (MRD1), EFS and overall survival (OS). ADE response score equation was further validated using RNA-Seq gene-expression data obtained from diagnostic samples of 432 pediatric AML patients enrolled in Children's Oncology Group (COG) AAML0531 and AAML03P1 treatment protocols. Results: After applying LASSO regression, we defined the equation: ADE-RS = (0.128 x DCTD) - (0.0993 x TOP2A) + (0.212 x ABCC1) - (0.113 x MPO) - (0.126 x CBR1) to develop ADE-response score (ADE-RS), followed by classifying patients into low (60%; 98 patients) or high (40%; 65 patients) score groups. Patients in the high ADE-RS group had significantly worse EFS (HR=4.07(2.43-6.84), P &lt; 0.0001; Figure 1A) and OS (HR= 4.54(2.42-8.49), P&lt;0.0001) and higher proportion of MRD1 positive patients (P=0.014; Figure 1B) compared to patients in the low ADE-RS group. These results were validated in an independent COG cohort, where patients in the high score group demonstrated higher MRD1 positivity (P=0.0005; Figure 1D) and inferior EFS (HR=1.32(1.01-1.73), P=0.044; Figure 1C). We recently developed a six-gene leukemic stem cell score (pLSC6 score) that was associated with risk-groups (P&lt;0.00001) and outcome (oral presentation ASH2018, Under-review, Leukemia). We further integrated pLSC6 and ADE-RS and observed significantly better prediction of treatment outcomes in AML02, COG and TCGA cohorts. Based on pLSC6 and ADE-response scores, patients were classified into three groups; 1) Low/Low:pLSC6/ADE-RS; for patients with low pLSC6 and low ADE-RS. 2) Low/High:pLSC6/ADE-RS: for patients in low pLSC6 and high ADE-RS or vice versa.3) High/High:pLSC6/ADE-RS: for patients in high pLSC6 and high ADE-RS. In all study cohorts, patients in low/low pLSC6-ADE-RS group demonstrated better outcomes compared to the low-high and the high/high score groups (EFS in AML02 cohort; Figure 1E and OS; Figure 1F). In a multivariable cox-regression models that included pLSC6-ADE response score groups, MRD1 status, risk groups, WBC at diagnosis and age in AML02 cohort, high pLSC6-ADE score group was found significantly associated with poor EFS (HR=6.02(2.71-13.2), P&lt;0.00001; Figure 1G) and was the only significant predictor of poor OS (HR=8.3(2.9-23.99), P&lt;0.00001; Figure 1H) Discussion: In this study, we defined a pharmacological response score focused on key genes of PK/PD significance to ADE. We further integrated LSC score with the ADE response score to improve our ability to predict treatment outcome in AML patients across different clinical trials. ADE-RS was composed of five genes: DCTD, which is a deaminase, involved in ara-C inactivation; CBR1, a carbonyl reductase involved in inactivation of daunorubicin (DNR); MPO, myeloperoxidase, an etoposide activator; ABCC1, an efflux transporter of DNR and etoposide; and TOP2A, DNA topoisomerase II alpha, which is a target for DNR and etoposide. Integrated pLSC6 and ADE-RS has a potential to predict treatment outcomes using diagnostic gene expression levels and accordingly develop treatment strategies to improve treatment outcome. Figure 1 Disclosures Gruber: Bristol-Myers Squibb: Consultancy. Rubnitz:AbbVie: Research Funding.
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Larkin, Trisha, Abdelrahman H. Elsayed, Roya Rafiee, Natasha Emanuel, Beate Greer, Biljana N. Horn, and Jatinder K. Lamba. "Identification of Pharmacogenomic Single Nucleotide Polymorphism Variants As Contributors to Toxicity Phenotype in the Treatment of Acute Childhood Leukemia." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-143195.

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Introduction: Despite more than 80% long-term survival in acute lymphoblastic leukemia (ALL), morbidity due to drug-related toxicities remains high. Treatment interruptions and omissions from these toxicities may affect survivorship outcomes and morbidities in pediatric cancer. Although multiple factors contribute to a patient's risk of toxicity pharmacogenetic factors have been shown to play critical roles. Genetic variation within genes involved in pharmacokinetic and pharmacodynamic pathways of chemotherapies can influence gene expression and/or activity resulting in inter-patient variation in drug levels and thus toxicity risk or therapeutic efficacy. Identification of SNPs of clinical relevance that are predictive of toxicity can allow clinicians to optimize therapy to manage toxicity phenotypes. Objective: The objective of this cross-sectional study was to explore pharmacogenomic biomarkers associated with clinically relevant toxicity phenotypes in children receiving ALL therapy. Methods: The protocol was approved by the University of Florida (UF) Institutional Review Board (IRB201802623). All participants provided informed consent. Patients ≤ 26 years of age with a diagnosis of de novo or secondary ALL and who had received induction and consolidation chemotherapy after May 2012 at UF were eligible for participation. Chart review was performed and CTCAE-graded toxicity data was abstracted for gastrointestinal (GI), neurological, and endocrine toxicities along with prolonged hospitalization (&gt; 4 days) due to febrile neutropenia. Genomic DNA was obtained from peripheral blood. SNPs in candidate pharmacological genes in cytarabine, vincristine, methotrexate, daunorubicin/doxorubicin, mercaptopurine/thioguanine pathways were selected through literature search and PharmGKB database. Genotyping was performed using Sequenom-based based chemistry. SNPs with low call rate and minor allele frequency of &lt;0.10 were filtered and 105 SNPs were tested for association with each toxicity endpoint using logistic regression models with additive, dominant, and recessive modes of inheritance. Odds ratio (OR) and 95% confidence interval were calculated for each test. SNPs with association P-value &lt; 0.05 were considered significant. Results: Prevalence of toxicity and top genes with significant SNPs are summarized in Figure 1. SNP in a carbonyl reductase (CBR1) involved in anthracycline metabolism was associated with higher risk of GI toxicity (OR 2.49, p=0.016). Multiple SNPs in cytarabine pathway genes were associated with increased risk of GI toxicities (rs12067645 in CTPS1, rs11853372 in SLC28A1 and rs10916819 in CDA) whereas SNP in an influx transporter SLCO1B1, implicated in methotrexate uptake was associated with lower risk of GI toxicity (rs2291075, OR 0.224, p =0.017). Six SNPs were associated with higher incidence of hematological toxicity with most interesting SNP being rs12067645 in CTPS1, a gene involved in cytarabine metabolism (OR 5.89, p=0.026). rs1128503 in drug efflux transporter ABCB1, rs2228110 in ALDH3A1, and rs2853539 in TYMS were all associated with lower incidence of neurologic toxicities. rs4673 in CYBA (OR 3.76, p=0.015) associated with higher neurological toxicity. Of the 5 SNPs associated with endocrinopathies, 4 were associated with increased and one with reduced incidence of toxicity. Interestingly, 2 SNPs in cytarabine uptake transporter SLC29A1, rs507964 (OR 2.89, p=0.02) and rs324148 (OR 1.89, p=0.042) and one missense SNP rs1051266 in SLC19A implicated in methotrexate influx was predictive of prolonged hospitalizations from febrile neutropenia. Figure 1 highlights some of these results. Conclusion: In conclusion, we identified common SNPs in genes associated with pharmacology of most commonly used anti-leukemic agents that were predictive of interpatient variability in incidence of drug toxicity phenotypes in a pilot cohort of 51 patients with ALL. Though limited by sample size, our studies demonstrate exciting results with ongoing enrollment and analysis showing promise in developing a SNP based model for prediction of toxicity in pediatric patients. Our goal is to integrate SNPs into a toxicity score for each patient which, once validated in collaborative multi-site cohorts, will hold value when transitioned to the clinic for personalizing treatment regimens to achieve therapeutic benefit and minimize morbidities. Disclosures No relevant conflicts of interest to declare.
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Bateman, Raynard L., Daniel Rauh, Brandon Tavshanjian, and Kevan M. Shokat. "Human Carbonyl Reductase 1 Is anS-Nitrosoglutathione Reductase." Journal of Biological Chemistry 283, no. 51 (September 29, 2008): 35756–62. http://dx.doi.org/10.1074/jbc.m807125200.

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Miura, Takeshi, Toru Nishinaka, and Tomoyuki Terada. "Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1." Molecular and Cellular Biochemistry 315, no. 1-2 (May 21, 2008): 113–21. http://dx.doi.org/10.1007/s11010-008-9794-5.

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33

Aplenc, R., J. Blanco, W. Leisenring, S. Davies, M. Relling, L. Robison, C. Sklar, M. Stovall, and S. Bhatia. "Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9004. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9004.

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9004 Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted. No significant financial relationships to disclose.
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Wayne, Laura L., and John Browse. "Homologous electron transport components fail to increase fatty acid hydroxylation in transgenic Arabidopsis thaliana." F1000Research 2 (October 4, 2013): 203. http://dx.doi.org/10.12688/f1000research.2-203.v1.

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Ricinoleic acid, a hydroxylated fatty acid (HFA) present in castor (Ricinus communis) seeds, is an important industrial commodity used in products ranging from inks and paints to polymers and fuels. However, due to the deadly toxin ricin and allergens also present in castor, it would be advantageous to produce ricinoleic acid in a different agricultural crop. Unfortunately, repeated efforts at heterologous expression of the castor fatty acid hydroxylase (RcFAH12) in the model plant Arabidopsis thaliana have produced only 17-19% HFA in the seed triacylglycerols (TAG), whereas castor seeds accumulate up to 90% ricinoleic acid in the endosperm TAG. RcFAH12 requires an electron supply from NADH:cytochrome b5 reductase (CBR1) and cytochrome b5 (Cb5) to synthesize ricinoleic acid. Previously, our laboratory found a mutation in the Arabidopsis CBR1 gene, cbr1-1, that caused an 85% decrease in HFA levels in the RcFAH12 Arabidopsis line. These results raise the possibility that electron supply to the heterologous RcFAH12 may limit the production of HFA. Therefore, we hypothesized that by heterologously expressing RcCb5, the reductant supply to RcFAH12 would be improved and lead to increased HFA accumulation in Arabidopsis seeds. Contrary to this proposal, heterologous expression of the top three RcCb5 candidates did not increase HFA accumulation. Furthermore, coexpression of RcCBR1 and RcCb5 in RcFAH12 Arabidopsis also did not increase in HFA levels compared to the parental lines. These results demonstrate that the Arabidopsis electron transfer system is supplying sufficient reductant to RcFAH12 and that there must be other bottlenecks limiting the accumulation of HFA.
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Wayne, Laura L., and John Browse. "Homologous electron transport components fail to increase fatty acid hydroxylation in transgenic Arabidopsis thaliana." F1000Research 2 (November 13, 2013): 203. http://dx.doi.org/10.12688/f1000research.2-203.v2.

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Анотація:
Ricinoleic acid, a hydroxylated fatty acid (HFA) present in castor (Ricinus communis) seeds, is an important industrial commodity used in products ranging from inks and paints to polymers and fuels. However, due to the deadly toxin ricin and allergens also present in castor, it would be advantageous to produce ricinoleic acid in a different agricultural crop. Unfortunately, repeated efforts at heterologous expression of the castor fatty acid hydroxylase (RcFAH12) in the model plant Arabidopsis thaliana have produced only 17-19% HFA in the seed triacylglycerols (TAG), whereas castor seeds accumulate up to 90% ricinoleic acid in the endosperm TAG. RcFAH12 requires an electron supply from NADH:cytochrome b5 reductase (CBR1) and cytochrome b5 (Cb5) to synthesize ricinoleic acid. Previously, our laboratory found a mutation in the Arabidopsis CBR1 gene, cbr1-1, that caused an 85% decrease in HFA levels in the RcFAH12 Arabidopsis line. These results raise the possibility that electron supply to the heterologous RcFAH12 may limit the production of HFA. Therefore, we hypothesized that by heterologously expressing RcCb5, the reductant supply to RcFAH12 would be improved and lead to increased HFA accumulation in Arabidopsis seeds. Contrary to this proposal, heterologous expression of the top three RcCb5 candidates did not increase HFA accumulation. Furthermore, coexpression of RcCBR1 and RcCb5 in RcFAH12 Arabidopsis also did not increase in HFA levels compared to the parental lines. These results demonstrate that the Arabidopsis electron transfer system is supplying sufficient reductant to RcFAH12 and that there must be other bottlenecks limiting the accumulation of HFA.
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Boušová, Iva, Lenka Skálová, Pavel Souček, and Petra Matoušková. "The modulation of carbonyl reductase 1 by polyphenols." Drug Metabolism Reviews 47, no. 4 (September 29, 2015): 520–33. http://dx.doi.org/10.3109/03602532.2015.1089885.

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Carlquist, Magnus, Torbjörn Frejd, and Marie F. Gorwa-Grauslund. "Flavonoids as inhibitors of human carbonyl reductase 1." Chemico-Biological Interactions 174, no. 2 (July 2008): 98–108. http://dx.doi.org/10.1016/j.cbi.2008.05.021.

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38

Kassner, Nina, Klaus Huse, Hans-Jörg Martin, Ute Gödtel-Armbrust, Annegret Metzger, Ingolf Meineke, Jürgen Brockmöller, et al. "Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver." Drug Metabolism and Disposition 36, no. 10 (July 17, 2008): 2113–20. http://dx.doi.org/10.1124/dmd.108.022251.

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39

Tang, Xianqing, Peiqiang Mu, Jun Wu, Jun Jiang, Caihui Zhang, Ming Zheng, and Yiqun Deng. "Carbonyl Reduction of Mequindox by Chicken and Porcine Cytosol and Cloned Carbonyl Reductase 1." Drug Metabolism and Disposition 40, no. 4 (January 19, 2012): 788–95. http://dx.doi.org/10.1124/dmd.111.043547.

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40

Moschini, Roberta, Rossella Rotondo, Giovanni Renzone, Francesco Balestri, Mario Cappiello, Andrea Scaloni, Umberto Mura, and Antonella Del-Corso. "Kinetic features of carbonyl reductase 1 acting on glutathionylated aldehydes." Chemico-Biological Interactions 276 (October 2017): 127–32. http://dx.doi.org/10.1016/j.cbi.2017.03.003.

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41

Shi, Sophia M., and Li Di. "The role of carbonyl reductase 1 in drug discovery and development." Expert Opinion on Drug Metabolism & Toxicology 13, no. 8 (July 27, 2017): 859–70. http://dx.doi.org/10.1080/17425255.2017.1356820.

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42

Varatharajan, Savitha, Ajay Abraham, Wei Zhang, R. V. Shaji, Rayaz Ahmed, Aby Abraham, Biju George, et al. "Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia." European Journal of Clinical Pharmacology 68, no. 12 (May 5, 2012): 1577–86. http://dx.doi.org/10.1007/s00228-012-1291-9.

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43

Ramsden, Diane, Dustin Smith, Raquel Arenas, Kosea Frederick, and Matthew A. Cerny. "Identification and Characterization of a Selective Human Carbonyl Reductase 1 Substrate." Drug Metabolism and Disposition 46, no. 10 (August 1, 2018): 1434–40. http://dx.doi.org/10.1124/dmd.118.082487.

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44

Moschini, Roberta, Giovanni Renzone, Vito Barracco, Mario Cappiello, Andrea Scaloni, Francesco Balestri, Umberto Mura, and Antonella Del-Corso. "A new role for Carbonyl Reductase 1 on 4-hydroxynonenal detoxification." Free Radical Biology and Medicine 124 (August 2018): 572. http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.047.

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45

Hintzpeter, Jan, Jan Hornung, Bettina Ebert, Hans-Jörg Martin, and Edmund Maser. "Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – Carbonyl reductase 1." Chemico-Biological Interactions 234 (June 2015): 162–68. http://dx.doi.org/10.1016/j.cbi.2014.12.019.

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46

Barracco, Vito, Roberta Moschini, Giovanni Renzone, Mario Cappiello, Francesco Balestri, Andrea Scaloni, Umberto Mura, and Antonella Del-Corso. "Dehydrogenase/reductase activity of human carbonyl reductase 1 with NADP(H) acting as a prosthetic group." Biochemical and Biophysical Research Communications 522, no. 1 (January 2020): 259–63. http://dx.doi.org/10.1016/j.bbrc.2019.11.090.

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47

Biswas, Md Sanaullah, Ryota Terada, and Jun’ichi Mano. "Inactivation of Carbonyl-Detoxifying Enzymes by H2O2 Is a Trigger to Increase Carbonyl Load for Initiating Programmed Cell Death in Plants." Antioxidants 9, no. 2 (February 6, 2020): 141. http://dx.doi.org/10.3390/antiox9020141.

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Анотація:
H2O2-induced programmed cell death (PCD) of tobacco Bright Yellow-2 (BY-2) cells is mediated by reactive carbonyl species (RCS), degradation products of lipid peroxides, which activate caspase-3-like protease (C3LP). Here, we investigated the mechanism of RCS accumulation in the H2O2-induced PCD of BY-2 cells. The following biochemical changes were observed in 10-min response to a lethal dose (1.0 mM) of H2O2, but they did not occur in a sublethal dose (0.5 mM) of H2O2. (1) The C3LP activity was increased twofold. (2) The intracellular levels of RCS, i.e., 4-hydroxy-(E)-hexenal and 4-hydroxy-(E)-nonenal (HNE), were increased 1.2–1.5-fold. (3) The activity of a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent carbonyl reductase, scavenging HNE, and n-hexanal was decreased. Specifically, these are the earliest events leading to PCD. The proteasome inhibitor MG132 suppressed the H2O2-induced PCD, indicating that the C3LP activity of the β1 subunit of the 20S proteasome was responsible for PCD. The addition of H2O2 to cell-free protein extract inactivated the carbonyl reductase. Taken together, these results suggest a PCD-triggering mechanism in which H2O2 first inactivates a carbonyl reductase(s), allowing RCS levels to rise, and eventually leads to the activation of the C3LP activity of 20S proteasome. The carbonyl reductase thus acts as an ROS sensor for triggering PCD.
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48

Alshogran, Osama, Bradley Urquhart, and Thomas Nolin. "Downregulation of Hepatic Carbonyl Reductase Type 1 in End-Stage Renal Disease." Drug Metabolism Letters 9, no. 2 (October 27, 2015): 111–18. http://dx.doi.org/10.2174/1872312809666150818111626.

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49

Lu, Yuan, Wen Liu, Ting Lv, Yanli Wang, Ting Liu, Yi Chen, Yang Jin, et al. "Aidi injection reduces doxorubicin-induced cardiotoxicity by inhibiting carbonyl reductase 1 expression." Pharmaceutical Biology 60, no. 1 (August 18, 2022): 1616–24. http://dx.doi.org/10.1080/13880209.2022.2110127.

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50

OSAWA, YUKI, YOSHIHITO YOKOYAMA, TATSUHIKO SHIGETO, MASAYUKI FUTAGAMI, and HIDEKI MIZUNUMA. "Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation." International Journal of Oncology 46, no. 3 (December 30, 2014): 1252–58. http://dx.doi.org/10.3892/ijo.2014.2810.

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