Journal articles: 'CYP199A4'

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Chao, Rebecca R., James J. De Voss, and Stephen G. Bell. "The efficient and selective catalytic oxidation of para-substituted cinnamic acid derivatives by the cytochrome P450 monooxygenase, CYP199A4." RSC Advances 6, no. 60 (2016): 55286–97. http://dx.doi.org/10.1039/c6ra11025h.

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Coleman, Tom, Rebecca R. Chao, John B. Bruning, James J. De Voss, and Stephen G. Bell. "CYP199A4 catalyses the efficient demethylation and demethenylation of para-substituted benzoic acid derivatives." RSC Advances 5, no. 64 (2015): 52007–18. http://dx.doi.org/10.1039/c5ra08730a.

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CYP199A4, a cytochrome P450 enzyme from Rhodopseudomonas palustris HaA2, is able to efficiently demethylate a range of benzoic acids at the para-position. It can also catalyse demethenylation reactions.

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Faletrov, Y. V., V. O. Maliugin, N. S. Frolova, and V. M. Shkumatov. "<i>In silico</i> evaluation of new affine interactions of methylcoumarin with cytochromes P450." Proceedings of the National Academy of Sciences of Belarus, Chemical Series 58, no. 2 (June 8, 2022): 186–90. http://dx.doi.org/10.29235/1561-8331-2022-58-2-186-190.

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4-methyl-7-methoxycoumarin (CumOMe) has been synthesized and in silico calculations demonstrated localization of methoxy group within 0.4 nm from Fe ion of hem groups for some structures of human CYP19 & CYP46 as well as CYP152 S. paucimobilis, CYP158 St. coelicolor, HMUO C. diphtheriae, XPLA R. rhodochrous, CYP199A4 Rh. palustris, CYP101A1 Ps. putida and CYP51 M. tuberculosis.

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Bell, Stephen G., Wen Yang, Adrian B. H. Tan, Ruimin Zhou, Eachan O. D. Johnson, Aili Zhang, Weihong Zhou, Zihe Rao, and Luet-Lok Wong. "The crystal structures of 4-methoxybenzoate bound CYP199A2 and CYP199A4: structural changes on substrate binding and the identification of an anion binding site." Dalton Transactions 41, no. 28 (2012): 8703. http://dx.doi.org/10.1039/c2dt30783a.

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Bell, Stephen G., Adrian B. H. Tan, Eachan O. D. Johnson, and Luet-Lok Wong. "Selective oxidative demethylation of veratric acid to vanillic acid by CYP199A4 from Rhodopseudomonas palustris HaA2." Mol. BioSyst. 6, no. 1 (2009): 206–14. http://dx.doi.org/10.1039/b913487e.

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Coleman, Tom, Siew Hoon Wong, Matthew N. Podgorski, John B. Bruning, James J. De Voss, and Stephen G. Bell. "Cytochrome P450 CYP199A4 from Rhodopseudomonas palustris Catalyzes Heteroatom Dealkylations, Sulfoxidation, and Amide and Cyclic Hemiacetal Formation." ACS Catalysis 8, no. 7 (May 17, 2018): 5915–27. http://dx.doi.org/10.1021/acscatal.8b00909.

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Coleman, Tom, Rebecca R. Chao, James J. De Voss, and Stephen G. Bell. "The importance of the benzoic acid carboxylate moiety for substrate recognition by CYP199A4 from Rhodopseudomonas palustris HaA2." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1864, no. 6 (June 2016): 667–75. http://dx.doi.org/10.1016/j.bbapap.2016.03.006.

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Vanselow, Jens, Alan J. Conley, Cynthia J. Corbin, and Trish Berger. "Genomic Structure of the Porcine CYP19 Locus and Expression of the CYP19A3 Paralog." Genes 12, no. 4 (April 6, 2021): 533. http://dx.doi.org/10.3390/genes12040533.

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Proper, tissue-specific regulation of CYP19, the gene encoding aromatase, the key enzyme of estrogen synthesis, is essential for reproductive processes. Here, we analyzed transcriptional regulation of the porcine CYP19 in female and male gonads and brain by 5’RACE and RT-PCR and comprehensively mapped the pig CYP19 locus by in silico analysis. Our data revealed that the complete locus, including three paralogous copies, CYP19A1, CYP19A2 and CYP19A3, spans approximately 330 kb of the porcine chromosome 1. The locus also harbors the first exon of the Gliomedin gene (GLDN) in reverse orientation. Only transcripts of the CYP19A3 paralog were substantially expressed in gonads and hypothalamus. We identified CYP19A3-associated untranslated exons approximately 160 kb and 50 kb distal from the first codon. The 5´ untranslated regions of transcripts were derived from either a proximal or from one of these distal untranslated exons. Transcripts including only untranslated exons could be amplified from testis, thus suggesting long non-coding transcripts. The data revealed an additional layer of complexity in the regulation of the porcine CYP19 locus. Tissue-specific expression is not only achieved by tissue- and stage-specific expression of the three different CYP19 paralogs, but also by directing the expression of CYP19A3 from different, proximal and distal promoter regions.

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Bell, Stephen G., Ruimin Zhou, Wen Yang, Adrian B. H. Tan, Alexander S. Gentleman, Luet-Lok Wong, and Weihong Zhou. "Investigation of the Substrate Range of CYP199A4: Modification of the Partition between Hydroxylation and Desaturation Activities by Substrate and Protein Engineering." Chemistry - A European Journal 18, no. 52 (November 7, 2012): 16677–88. http://dx.doi.org/10.1002/chem.201202776.

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Kazeto, Yukinori, Shigeho Ijiri, Allen R. Place, Yonathan Zohar, and John M. Trant. "The 5′-Flanking Regions of CYP19A1 and CYP19A2 in Zebrafish." Biochemical and Biophysical Research Communications 288, no. 3 (November 2001): 503–8. http://dx.doi.org/10.1006/bbrc.2001.5796.

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Kazeto, Y., and J. M. Trant. "Molecular biology of channel catfish brain cytochrome P450 aromatase (CYP19A2): cloning, preovulatory induction of gene expression, hormonal gene regulation and analysis of promoter region." Journal of Molecular Endocrinology 35, no. 3 (December 2005): 571–83. http://dx.doi.org/10.1677/jme.1.01805.

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Cytochrome P450 aromatase (CYP19) converts androgens to estrogens. Unlike mammals, teleosts have two CYP19 genes, expressed differentially in ovary (CYP19A1) and neuronal tissues (CYP19A2). The primary purpose of this study was to demonstrate the potential involvement of CYP19A2 in the reproductive endocrinology of teleosts. Channel catfish CYP19A2 (ccCYP19A2) cDNAs were isolated from the brain using a PCR-based strategy. The ccCYP19A2 cDNA putatively encodes 500 amino acids which conferred aromatase activity in transfected COS-7 cells. Additionally, an alternatively spliced transcript was isolated which lacks the first 122 amino acids and is catalytically inactive. The brain and the pituitary were predominant sources of ccCYP19A2 transcript and the abundance in both tissues acutely increased prior to spawning. This preovulatory induction of ccCYP19A2 gene in the pituitary is remarkably similar to the pattern of gene expression for luteinizing hormone-β (LHβ). Estradiol-17β (E2) and testosterone enhanced the transcript abundance of ccCYP19A2 and LHβ in catfish pituitary cells cultured in vitro but the stimulatory effects of testosterone were abolished by an aromatase inhibitor, indicating an important role of E2, the product of CYP19A2 activity, in the regulation of CYP19A2 and LHβ. Structural and functional analysis of the 5′-flanking region of the gene suggested that the sequence from −1076 to − 435 bp is critical for the basal promoter activity in the pituitary. This report demonstrates that CYP19A2 functions as an important factor in the reproductive endocrinology of teleosts through the brain-pituitary-gonadal axis.

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Dong, Wu, and Kristine L. Willett. "Local expression of CYP19A1 and CYP19A2 in developing and adult killifish (Fundulus heteroclitus)." General and Comparative Endocrinology 155, no. 2 (January 2008): 307–17. http://dx.doi.org/10.1016/j.ygcen.2007.05.018.

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Bimonte, Viviana M., Francesco Marampon, Ambra Antonioni, Simona Fittipaldi, Elisabetta Ferretti, Richard G. Pestell, Mariaignazia Curreli, et al. "Phosphodiesterase Type-5 Inhibitor Tadalafil Modulates Steroid Hormones Signaling in a Prostate Cancer Cell Line." International Journal of Molecular Sciences 22, no. 2 (January 13, 2021): 754. http://dx.doi.org/10.3390/ijms22020754.

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Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Results: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.

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Jędrzejczak, M., I. Szatkowska, S. Zych, W. Grzesiak, E. Czerniawska-Piątkowska, and A. Dybus. "Evaluation of associations of the polymorphism in the placentaspecific promoter 1.1 of the <i>CYP19</i> gene in Black-and-White and Jersey cattle with milk production traits (short communication)." Archives Animal Breeding 49, no. 4 (October 10, 2006): 311–14. http://dx.doi.org/10.5194/aab-49-311-2006.

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Abstract. The relationship between the SNP of the cytochrome P450 gene (CYP19-PvuII) and milk production traits of Black-and-White and Jersey cattle were analysed. A total of 437 cows were included in the study. A PCR-RFLP was used to genotype. The frequencies of genotypes and alleles for the Black-and-White cows were as follows: 0.8985 – AA, 0.0977 – AB, 0.0038 – BB, and 0.9474 – CYP19A, 0.0526 – CYP19B. In the Jersey, all cows were genotyped as CYP19AA (no polymorphism). There weren’t any associations between CYP19-PvuII polymorphism and milk production traits of the investigated cows.

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Furuya, Toshiki, Yuka Arai, and Kuniki Kino. "Biotechnological Production of Caffeic Acid by Bacterial Cytochrome P450 CYP199A2." Applied and Environmental Microbiology 78, no. 17 (June 22, 2012): 6087–94. http://dx.doi.org/10.1128/aem.01103-12.

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ABSTRACTCaffeic acid is a biologically active molecule that has various beneficial properties, including antioxidant, anticancer, and anti-inflammatory activities. In this study, we explored the catalytic potential of a bacterial cytochrome P450, CYP199A2, for the biotechnological production of caffeic acid. When the CYP199A2 enzyme was reacted withp-coumaric acid, it stoichiometrically produced caffeic acid. The crystal structure of CYP199A2 shows that Phe at position 185 is situated directly above, and only 6.35 Å from, the heme iron. This F185 residue was replaced with hydrophobic or hydroxylated amino acids using site-directed mutagenesis to create mutants with novel and improved catalytic properties. In whole-cell assays with the known substrate of CYP199A2, 2-naphthoic acid, only the wild-type enzyme hydroxylated 2-naphthoic acid at the C-7 and C-8 positions, whereas all of the active F185 mutants exhibited a preference for C-5 hydroxylation. Interestingly, several F185 mutants (F185V, F185L, F185I, F185G, and F185A mutants) also acquired the ability to hydroxylate cinnamic acid, which was not hydroxylated by the wild-type enzyme. These results demonstrate that F185 is an important residue that controls the regioselectivity and the substrate specificity of CYP199A2. Furthermore,Escherichia colicells expressing the F185L mutant exhibited 5.5 times higher hydroxylation activity forp-coumaric acid than those expressing the wild-type enzyme. By using the F185L whole-cell catalyst, the production of caffeic acid reached 15 mM (2.8 g/liter), which is the highest level so far attained in biotechnological production of this compound.

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Zhang, Yan, Xiang Chen, Zhinan Zhou, Xingzhou Tian, Peifang Yang, and Kaibing Fu. "CYP19A1 May Influence Lambing Traits in Goats by Regulating the Biological Function of Granulosa Cells." Animals 12, no. 15 (July 27, 2022): 1911. http://dx.doi.org/10.3390/ani12151911.

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Abnormal expression of CYP19A1, a gene related to steroid hormone synthesis, causes steroid hormone disruption and leads to abnormal ovulation in granulosa cells. However, the exact mechanism of CYP19A1 regulation is unclear. In this study, we confirmed the localization of CYP19A1 in goat ovarian tissues using immunohistochemistry. Subsequently, we investigated the effects of CYP19A1 on granulosa cell proliferation, steroid hormone secretion, and expression of candidate genes for multiparous traits by overexpressing and silencing CYP19A1 in goat granulosa cells (GCs). The immunohistochemistry results showed that CYP19A1 was expressed in all types of follicular, luteal, and granulosa cells, with subcellular localization results revealing that CYP19A1 protein was mainly localized in the cytoplasm and nucleus. Overexpression of CYP19A1 significantly increased the mRNA levels of CYP19A1, FSHR, and INHBA, which are candidate genes for multiple birth traits in goats. It also promoted cell proliferation, PCNA and Cyclin E mRNA levels in granulosa cells, and secretion of estrogen and progesterone. However, it inhibited the mRNA levels of STAR, CYP11A1, and 3βSHD, which are genes related to steroid synthesis. Silencing CYP19A1 expression significantly reduced CYP19A1, FSHR, and INHBA mRNA levels in granulosa cells and inhibited granulosa cell proliferation and PCNA and Cyclin E mRNA levels. It also reduced estrogen and progesterone secretion but enhanced the mRNA levels of STAR, CYP11A1, and 3βSHD. CYP19A1 potentially influenced the lambing traits in goats by affecting granulosa cell proliferation, hormone secretion, and expression of candidate genes associated with traits for multiple births.

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Li, Huitao, Yu Zhao, Lanlan Chen, Ying Su, Xiaoheng Li, Lixu Jin, and Ren-Shan Ge. "Triclocarban and Triclosan Inhibit Human Aromatase via Different Mechanisms." BioMed Research International 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8284097.

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Human aromatase (CYP19A1) is an important enzyme, which produces estrogen from androgen for maintaining the female reproductive function and pregnancy. Triclocarban and triclosan are antimicrobial chemicals added to personal care, household, and industrial products. They could be endocrine disruptors and may disrupt human CYP19A1 activity. In the present study, we investigated the effects of triclocarban and triclosan on estradiol production and human CYP19A1 activity in JEG-3 cells. Triclocarban and triclosan reduced estradiol production in JEG-3 cells. Triclocarban and triclosan inhibited human CYP19A1 with IC50values of 15.81 and 6.26 μM, respectively. Triclosan competitively inhibited CYP19A1, while triclocarban noncompetitively inhibited this enzyme. Docking study showed that triclosan bound to the steroid-binding pocket of CYP19A1, while triclocarban was off this target, suggesting a different mechanism. In conclusion, triclocarban and triclosan are inhibitors of human CYP19A1.

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Meyer, Ashley E., Caroline A. Pfeiffer, Kelsey E. Brooks, Lee D. Spate, Joshua A. Benne, Raissa Cecil, Melissa S. Samuel, et al. "New perspective on conceptus estrogens in maternal recognition and pregnancy establishment in the pig†." Biology of Reproduction 101, no. 1 (April 10, 2019): 148–61. http://dx.doi.org/10.1093/biolre/ioz058.

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Abstract The proposed signal for maternal recognition of pregnancy in pigs is estrogen (E2), produced by the elongating conceptuses between days 11 to 12 of pregnancy with a more sustained increase during conceptus attachment and placental development on days 15 to 30. To understand the role of E2 in porcine conceptus elongation and pregnancy establishment, a loss-of-function study was conducted by editing aromatase (CYP19A1) using CRISPR/Cas9 technology. Wild-type (CYP19A1+/+) and (CYP19A1−/−) fibroblast cells were used to create embryos through somatic cell nuclear transfer, which were transferred into recipient gilts. Elongated and attaching conceptuses were recovered from gilts containing CYP19A1+/+ or CYP19A1−/− embryos on day 14 and 17 of pregnancy. Total E2 in the uterine flushings of gilts with CYP19A1−/− embryos was lower than recipients containing CYP19A1+/+ embryos with no difference in testosterone, PGF2α, or PGE2 on either day 14 or 17. Despite the loss of conceptus E2 production, CYP19A1−/− conceptuses were capable of maintaining the corpora lutea. However, gilts gestating CYP19A1−/− embryos aborted between days 27 and 31 of gestation. Attempts to rescue the pregnancy of CYP19A1−/− gestating gilts with exogenous E2 failed to maintain pregnancy. However, CYP19A1−/− embryos could be rescued when co-transferred with embryos derived by in vitro fertilization. Endometrial transcriptome analysis revealed that ablation of conceptus E2 resulted in disruption of a number biological pathways. Results demonstrate that intrinsic E2 conceptus production is not essential for pre-implantation development, conceptus elongation, and early CL maintenance, but is essential for maintenance of pregnancy beyond 30 days .

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Ge, Hongshan, Lanlan Chen, Ying Su, Chunyan Jin, and Ren-Shan Ge. "Effects of Folpet, Captan, and Captafol on Human Aromatase in JEG-3 Cells." Pharmacology 102, no. 1-2 (2018): 81–87. http://dx.doi.org/10.1159/000484171.

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Background: Estradiol, produced by aromatase (CYP19A1), is very important for reproduction. Folpet, captan, and captafol belong to the phthalimide class of fungicides. They are used to protect the leaves of plants or fruits. They could be endocrine disruptors and may disrupt CYP19A1 activity. Methods: In the present study, we investigated the effects of folpet, captan, and captafol on estradiol production and human CYP19A1 activity in JEG-3 cells. Results: Folpet, captan, and captafol decreased estradiol production in JEG-3 cells in a concentration-dependent manner. Folpet, captan, and captafol inhibited human CYP19A1 with inhibitory concentration (IC50) values of 3.55, 10.68, and 1.14 μmol/L respectively. These chemicals competitively inhibited human CYP19A1. Molecular docking simulation analysis showed that they tended to bind to the steroid-binding pocket of the CYP19A1. However, the required concentrations may not be relevant to the negligible systemic exposures in humans to these chemicals. Conclusion: Folpet, captan, and captafol are potential inhibitors of human CYP19A1.

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Choi, Hyeonhae, Ki-Young Ryu, and Jaesook Roh. "Krüppel-like factor 4 plays a role in the luteal transition in steroidogenesis by downregulating Cyp19A1 expression." American Journal of Physiology-Endocrinology and Metabolism 316, no. 6 (June 1, 2019): E1071—E1080. http://dx.doi.org/10.1152/ajpendo.00238.2018.

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The transition from granulosa cell (GC) to luteal cell involves a change from estrogen production to predominantly progesterone production. We analyzed the role of Krüppel-like factor 4 ( Klf4), a transcriptional repressor used to generate pluripotent cells, in that transition. After luteinizing hormone (LH)/human chorionic gonadotropin treatment of preovulatory follicles, a major but transient increase in Klf4 transcript levels was detected. Therefore, we enquired whether Klf4 is involved in the rapid decline of aromatase, the key estrogen-producing enzyme, using preovulatory GCs obtained from pregnant mare serum gonadotropin-primed immature rat ovaries. Cyp19A1 expression in GCs transfected with FLAG- Klf4 or Klf4-specific siRNA was analyzed by real-time PCR and immunofluorescence staining. Cyp19A1 decreased when Klf4 was overexpressed, and Cyp19A1 and estradiol biosynthesis increased when Klf4 was knocked down. The mechanism by which Klf4 regulates Cyp19A1 expression was investigated using Cyp19A1 promoter-luciferase reporter assays and chromatin immunoprecipitation assays. The results revealed that the steroidogenic factor-1 (SF1)-binding motif, but not the specificity protein 1 (Sp1) binding element or the CACCC motif, was required for Klf4-mediated repression of Cyp19A1 promoter activity. Here we showed that Klf4 suppressed endogenous Cyp19A1 transcript and protein production, and this resulted from direct binding of Klf4 to the SF1 recognition motif in the Cyp19A1 promoter. These findings suggest that Klf4 is a physiologic regulator of Cyp19A1 expression in response to the LH surge in preovulatory GCs and that it has an essential role in the luteal transition in steroidogenesis.

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Chu, Ma, Sun, Zhu, Xiang, Yang, and Sun. "Leptin Receptor Mediates Bmal1 Regulation of Estrogen Synthesis in Granulosa Cells." Animals 9, no. 11 (November 1, 2019): 899. http://dx.doi.org/10.3390/ani9110899.

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Chronobiology affects female fertility in mammals. Lepr is required for leptin regulation of female reproduction. The presence of E-box elements in the Lepr promoter that are recognized and bound by clock genes to initiate gene transcription suggested that circadian systems might regulate fertility through Lepr. However, it is unclear whether Bmal1, a key oscillator controlling other clock genes, is involved in leptin regulation in hormone synthesis through Lepr. In this study, serum estradiol (E2) concentration and the expressions of Bmal1, Lepr, Cyp19a1, and Cyp11a1 genes were found to display well-synchronized circadian rhythms. Knockdown of Bmal1 significantly reduced expression levels of Lepr, Fshr, and Cyp19a1 genes; protein production of Bmal1, Lepr, and Cyp19a1; and the E2 concentration in granulosa cells. Knockdown of Lepr reduced the expression levels of Cyp19a1 and Cyp11a1 genes and Cyp19a1 protein, and also reduced E2 concentration. Addition of leptin affected the expression of Cyp19a1, Cyp11a1, and Fshr genes. Bmal1 deficiency counteracted leptin-stimulated upregulation of the genes encoding E2 synthesis in granulosa cells. These results demonstrated that Bmal1 participates in the process by which leptin acts on Lepr to regulate E2 synthesis.

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Gu, Yu, Wenbin Xu, Bole Zhuang, and Wei Fu. "Role of A-kinase anchoring protein 95 in the regulation of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) in human ovarian granulosa cells." Reproduction, Fertility and Development 30, no. 8 (2018): 1128. http://dx.doi.org/10.1071/rd17313.

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Irregular expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) is involved in the development of polycystic ovary syndrome (PCOS). Activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway plays a crucial role in FSH regulation of CYP19A1 in human ovarian granulosa cells. A-Kinase anchor protein 95 (AKAP95) is known to confine PKA to the nucleus. However, it is unclear whether anchoring PKA to the nucleus is essential for the induction of CYP19A1 by FSH in human ovarian granulosa cells. Using the human granulosa cell line KGN and primary cultured human luteinised granulosa cells (hLGCs), we found that knockdown of AKAP8, the gene encoding AKAP95, or inhibition of AKAP95 reduced the amount of PKA anchored in the nucleus and attenuated the phosphorylation of CREB by either FSH or activation of the cAMP/PKA pathway. Moreover, knockdown of AKAP8 or inhibition of AKAP95 also significantly attenuated FSH-induced CYP19A1 expression and oestrogen synthesis. Furthermore, significant decreases in AKAP95 and CYP19A1 were observed in hLGCs obtained from PCOS patients. The results of the present study demonstrate a crucial role for AKAP95 in CYP19A1 expression and oestrogen synthesis in hLGCs, which implies that AKAP95 may be involved in the pathogenesis of PCOS.

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Kudryavtseva, E. V., N. V. Kurbatova, V. V. Кovalev, and D. K. Islamidi. "Investigating genetic predisposition to premature decline in ovarian reserve." Obstetrics, Gynecology and Reproduction 16, no. 3 (July 12, 2022): 266–76. http://dx.doi.org/10.17749/2313-7347/ob.gyn.rep.2022.301.

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Introduction. Normal ovarian reserve (OR) determining the ovarian response to follicle development containing fully-featured oocytes is an important factor in pregnancy, including assisted reproductive technology (ART) programs. The causes of premature OR decrease are multifactorial. The study of gene polymorphism as a cause of the premature OR decrease deserves attention.Aim: to determine genetic predisposition to premature OR decrease and create a prognostic model based on study results.Materials and Methods. A retrospective comparative cohort study was conducted. A total of 200 reproductively active patients with infertility underwent ART were examined. The patients were divided into 2 groups: Group 1 included 100 patients with a premature OR decrease; Group 2 consisted of 100 patients with a normal OR. All patients underwent molecular genetic study. Genetic polymorphisms of the genes ESR1, ESR2, FSHR, CYP19A were studied.Results. The final clinical phenotype is shaped by multiple factors – genetic and environmental. Several genetic variants contribute to the formation of premature decrease in ovarian reserve. Gene combination of CYP19A1 and FSHR displayed the greatest synergistic effect, potentiating each other and predisposing to a poor ovarian response as part of stimulated superovulation.Conclusion. Identifying genetic markers is a promising method for individual OR evaluation, including its premature decline. Multilocus analysis and a prognostic model based on combining several polymorphic gene variants will allow to assess risks of premature OR decrease and individualize ART programs.

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FURUYA, Toshiki, and Kuniki KINO. "Biocatalytic Synthesis of Dihydroxynaphthoic Acids by Cytochrome P450 CYP199A2." Bioscience, Biotechnology, and Biochemistry 73, no. 12 (December 23, 2009): 2796–99. http://dx.doi.org/10.1271/bbb.90624.

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Lee, Lifa, Hiromi Asada, Fumie Kizuka, Isao Tamura, Ryo Maekawa, Toshiaki Taketani, Shun Sato, Yoshiaki Yamagata, Hiroshi Tamura, and Norihiro Sugino. "Changes in Histone Modification and DNA Methylation of the StAR and Cyp19a1 Promoter Regions in Granulosa Cells Undergoing Luteinization during Ovulation In Rats." Endocrinology 154, no. 1 (January 1, 2013): 458–70. http://dx.doi.org/10.1210/en.2012-1610.

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The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells (GCs) undergoing luteinization during ovulation. This study investigated in vivo whether epigenetic mechanisms including histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression. GCs were obtained from rats treated with equine chorionic gonadotropin (CG) before (0 h) and after human (h)CG injection. StAR mRNA levels rapidly increased after hCG injection, reached a peak at 4 h, and then remained higher compared with 0 h until 12 h. Cyp19a1 mRNA levels gradually decreased after hCG injection and reached their lowest level at 12 h. A chromatin immunoprecipitation assay revealed that levels of histone-H4 acetylation (Ac-H4) and trimethylation of histone-H3 lysine-4 (H3K4me3) increased whereas H3K9me3 and H3K27me3 decreased in the StAR promoter after hCG injection. On the other hand, the levels of Ac-H3 and -H4 and H3K4me3 decreased, and H3K27me3 increased in the Cyp19a1 promoter after hCG injection. Chromatin condensation, which was analyzed using deoxyribonuclease I, decreased in the StAR promoter and increased in the Cyp19a1 promoter after hCG injection. A chromatin immunoprecipitation assay also showed that binding activities of CAATT/enhancer-binding protein β to the StAR promoter increased and binding activities of phosphorylated-cAMP response element binding protein to the Cyp19a1 promoter decreased after hCG injection. These results provide in vivo evidence that histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression by altering chromatin structure of the promoters in GCs undergoing luteinization during ovulation.

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Costermans, N. G. J., N. M. Soede, F. van Tricht, M. Blokland, B. Kemp, J. Keijer, and K. J. Teerds. "Follicular fluid steroid profile in sows: relationship to follicle size and oocyte quality†." Biology of Reproduction 102, no. 3 (November 30, 2019): 740–49. http://dx.doi.org/10.1093/biolre/ioz217.

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Abstract Identification of reliable characteristics of follicle quality and developmental competence has been pursued in numerous studies, but with inconsistent outcomes. Here, we aimed to identify these characteristics by analysis of the follicular fluid (FF) steroid profile in relation to cumulus-oocyte complex (COC) morphology and follicle size, followed by molecular substantiation. Multiparous sows at weaning were used to facilitate analysis at the start of the follicular phase of the oestrus cycle. Sows with a higher average follicle size (≥5 mm vs. < 5 mm) had a higher follicular fluid β-estradiol concentration, but did not differ in other measured steroids. Sows with high compared to low percentage high-quality COCs (<70% vs. ≥70% high-quality) had follicular fluid with a higher concentration of β-estradiol, 19-norandrostenedione, progesterone, and α-testosterone, while the concentration of cortisol was lower. Transcriptome analysis of granulosa cells of healthy follicles of sows with a high percentage high-quality COCs showed higher abundance of transcripts involved in ovarian steroidogenesis (e.g., CYP19A2 and 3, POR, VEGFA) and growth (IGF1) and differential abundance of transcripts involved in granulosa cell apoptosis (e.g., GADD45A, INHBB). Differences in aromatase transcript abundance (CYP19A1, 2 and 3) were confirmed at the protein level. In addition, sows with a high percentage high-quality COCs lost less weight during lactation and had higher plasma IGF1 concentration at weaning, which may have affected COC quality. To the best of our knowledge, this study is also the first to report the relation between FF steroid profile and COC quality.

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Fukami, Maki, Takayoshi Tsuchiya, Heike Vollbach, Kristy A. Brown, Shuji Abe, Shigeyuki Ohtsu, Martin Wabitsch, et al. "Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression." Journal of Clinical Endocrinology & Metabolism 98, no. 12 (December 1, 2013): E2013—E2021. http://dx.doi.org/10.1210/jc.2013-2520.

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Context: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. Objective: The aim of the study was to clarify such unsolved matters. Design, Setting, and Methods: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. Results: Novel rearrangements included simple duplication involving exons 1–10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, nonhomologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement-associated motifs. The rearrangements resided in early-replicating segments. Conclusions: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

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Smolarz, Beata, Tomasz Szaflik, Hanna Romanowicz, and Krzysztof Szyłło. "Polymorphisms in the 3 ′ UTR Region of ESR2 and CYP19A1 Genes and Its Influence on Allele-Specific Gene Expression in Endometriosis." Disease Markers 2020 (December 1, 2020): 1–7. http://dx.doi.org/10.1155/2020/8845704.

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Objectives. Endometriosis is supported by hormonal, immunological, and environmental factors. No specific marker for endometriosis has yet been identified. ESR2 and CYP19A1 genes play a major role in the hormonal control of endometriosis women, the development of which largely depends on steroid hormones. Aim. An analysis of ESR2 and CYP19A1 allele-specific gene expressions in the context of the risk for endometriosis occurrence. Methods. The study material included paraffin-embedded tissue specimens, collected from patients ( n = 100 ) with endometriosis. Blood samples from age-matched, endometriosis-free women ( n = 100 ) served as a control. the RT-PCR technique was performed to observe the expression of ESR2 and CYP19A1 genes. Moreover, Sanger’s sequencing method was applied for polymorphism analysis. Results. A set of 4 single-nucleotide polymorphisms (SNPs) was determined; all of them most significantly associated with endometriosis: rs4986938 (G>A)(chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15). There were no differences in the distribution of genotypes and alleles in the studied groups, taking into account ESR2 and CYP19A1 gene expressions. Conclusion. The ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility. Further analysis is needed to specify the role of these polymorphisms in the pathogenesis of endometriosis.

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Oh, Jong-Nam, Jae Yeon Hwang, Kwang-Hwan Choi, and Chang-Kyu Lee. "Treatment of aromatase (CYP19A1) inhibitor reduces fertility in porcine sperm." Zygote 24, no. 1 (January 26, 2015): 98–106. http://dx.doi.org/10.1017/s0967199414000781.

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SummaryTo ascertain whether aromatase (CYP19A1) expression is linked to sperm fertility of pigs, the present study determined the expression of the CYP19A1 gene in porcine sperm and its relationship with fertilization in vitro. First, to investigate its role in fertility, the presence of CYP19A1 of mRNA and protein expression in porcine sperm were confirmed by real-time (RT) or quantitative polymerase chain reaction (q-PCR) and by western blots. The expression levels were determined quantitatively using two sperm groups recovered by a Percoll gradient, which revealed that the sperm group with a low density had a higher penetration rate than that of the high-density group (P < 0.05). However, the expression level of CYP19A1 was not significantly different between the two groups. Secondly, to examine the effect of aromatase activity on fertilization, fresh semen was treated with a steroidal inhibitor, exemestane (50 μM for 0.5 h), followed by the dose- and time-dependent viability test. Our results clearly showed that an exemestane treatment effect (P < 0.05) was found for both the sperm-penetration rate and the oocyte cleavage rate. These results indicated that CYP19A1 could be involved in sperm fertility and its expression in sperm plays an important role in fertilization.

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Dewaele, Aurélie, Emilie Dujardin, Marjolaine André, Audrey Albina, Hélène Jammes, Frank Giton, Eli Sellem, Geneviève Jolivet, Eric Pailhoux, and Maëlle Pannetier. "Absence of Testicular Estrogen Leads to Defects in Spermatogenesis and Increased Semen Abnormalities in Male Rabbits." Genes 13, no. 11 (November 8, 2022): 2070. http://dx.doi.org/10.3390/genes13112070.

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Estrogens are steroid hormones produced by the aromatization of androgens by the aromatase enzyme, encoded by the CYP19A1 gene. Although generally referred to as “female sex hormones”, estrogen is also produced in the adult testes of many mammals, including humans. To better understand the function of estrogens in the male, we used the rabbit model which is an important biomedical model. First, the expression of CYP19A1 transcripts was localized mainly in meiotic germ cells. Thus, testicular estrogen appears to be produced inside the seminiferous tubules. Next, the cells expressing ESR1 and ESR2 were identified, showing that estrogens could exert their function on post-meiotic germ cells in the tubules and play a role during sperm maturation, since ESR1 and ESR2 were detected in the cauda epididymis. Then, CRISPR/Cas9 CYP19A1−/− genetically modified rabbits were analyzed. CYP19A1−/− males showed decreased fertility with lower sperm count associated with hypo-spermatogenesis and lower spermatid number. Germ/sperm cell DNA methylation was unchanged, while sperm parameters were affected as CYP19A1−/− males exhibited reduced sperm motility associated with increased flagellar defects. In conclusion, testicular estrogens could be involved in the spermatocyte–spermatid transition in the testis, and in the acquisition of sperm motility in the epididymis.

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Kim, So-Sun, David Nahm-Joon Kim, Chang-Ju Lee, Hae-Kyun Yoo, Soon-Gyu Byun, Hyun-Jeong Lim, Jin Choi, and Jang-Su Park. "The Potential Sex Determination Genes, Sox9a and Cyp19a, in Walleye Pollock (Gadus Chalcogrammus) Are Influenced by Water Temperature." Journal of Marine Science and Engineering 8, no. 7 (July 8, 2020): 501. http://dx.doi.org/10.3390/jmse8070501.

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Our aim was to study the relationship between the sex-determining genes, sox9a and cyp19a, and water temperature in Gadus chalcogrammus. We assessed the sex ratio based on the expression levels of sox9a and cyp19a at different water temperatures (5, 8, 11, and 14 °C) and at different stages of walleye pollock development (embryos, larvae, and juveniles). Next, we used immature walleye pollock to assess sox9a expression in males and cyp19a and vitellogenin (VTG) expression in females at different water temperatures. Males expressed sox9a in the gonadal tissues, while females expressed cyp19a in the gonadal tissues and VTG in the blood plasma. In the first experiment, cyp19a expression was higher at 5 °C and 8 °C, and sox9a expression was higher at 11 and 14 °C. In the second experiment, sox9a expression remained relatively stable, but cyp19a expression decreased with increasing temperature, decreasing significantly after 14 °C. Similar patterns were also observed for VTG expression. These results indicate that lower water temperatures increase cyp19a expression, which increases the female ratio. Higher water temperatures increase sox9a expression, which increases the male ratio. Therefore, this study highlights the potential of the sex-determining genes and the influence of water temperature.

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Wang, De-Shou, Tohru Kobayashi, Lin-Yan Zhou, Bindhu Paul-Prasanth, Shigeho Ijiri, Fumie Sakai, Kataaki Okubo, Ken-ichirou Morohashi, and Yoshitaka Nagahama. "Foxl2 Up-Regulates Aromatase Gene Transcription in a Female-Specific Manner by Binding to the Promoter as Well as Interacting with Ad4 Binding Protein/Steroidogenic Factor 1." Molecular Endocrinology 21, no. 3 (March 1, 2007): 712–25. http://dx.doi.org/10.1210/me.2006-0248.

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Abstract Increasing evidence suggests the crucial role of estrogen in ovarian differentiation of nonmammalian vertebrates including fish. The present study has investigated the plausible role of Foxl2 in ovarian differentiation through transcriptional regulation of aromatase gene, using monosex fry of tilapia. Foxl2 expression is sexually dimorphic, like Cyp19a1, colocalizing with Cyp19a1 and Ad4BP/SF-1 in the stromal cells and interstitial cells in gonads of normal XX and sex-reversed XY fish, before the occurrence of morphological sex differentiation. Under in vitro conditions, Foxl2 binds to the sequence ACAAATA in the promoter region of the Cyp19a1 gene directly through its forkhead domain and activates the transcription of Cyp19a1 with its C terminus. Foxl2 can also interact through the forkhead domain with the ligand-binding domain of Ad4BP/SF-1 to form a heterodimer and enhance the Ad4BP/SF-1 mediated Cyp19a1 transcription. Disruption of endogenous Foxl2 in XX tilapia by overexpression of its dominant negative mutant (M3) induces varying degrees of testicular development with occasional sex reversal from ovary to testis. Such fish display reduced expression of Cyp19a1 as well as a drop in the serum levels of 17β-estradiol and 11-ketotestosterone. Although the XY fish with wild-type tilapia Foxl2 (tFoxl2) overexpression never exhibited a complete sex reversal, there were significant structural changes, such as tissue degeneration, somatic cell proliferation, and induction of aromatase, with increased serum levels of 17β-estradiol and 11-ketotestosterone. Altogether, these results suggest that Foxl2 plays a decisive role in the ovarian differentiation of the Nile tilapia by regulating aromatase expression and possibly the entire steroidogenic pathway.

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Kasielska-Trojan, Anna, Michał Pietrusiński, Magdalena Bugaj-Tobiasz, Jerzy Strużyna, Maciej Borowiec, and Bogusław Antoszewski. "Genetic Factors of Idiopathic Gigantomastia: Clinical Implications of Aromatase and Progesterone Receptor Polymorphisms." Journal of Clinical Medicine 11, no. 3 (January 27, 2022): 642. http://dx.doi.org/10.3390/jcm11030642.

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The role of estrogen, progesterone, their receptors and aromatase in the development of the breast is well documented. In this study we examined the association of genetic variants of progesterone receptor (PGR) and aromatase (CYP19A1) genes with gigantomastia risk. We conducted a case-control study among 124 women: 60 with gigantomastia and 64 controls. We examined the single nucleotide polymorphisms (SNPs) for CYP19A1 (rs749292 and rs7172156) and PGR (rs1042838). Our results showed that allele G in rs749292 (CYP19A1) increased the risk of gigantomastia, but not significantly (p = 0.09). There is a correlation between rs1042838 (PGR) and waist-to-hip ratio (WHR) in women with gigantomastia-AC genotype correlates with lower WHR and CC with higher WHR. There were no correlations between the onset of gigantomastia, the age of menarche and the length of the menstrual cycle, and rs1042838, rs749292 and rs7172156. We did not find differences in the SNP of PGR (rs1042838) between women with gigantomastia and controls. However, our findings showed more frequent G allele in CYP19A1 (rs749292) in women with gigantomastia.

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Andric, Nebojsa, Mika Thomas, and Mario Ascoli. "Transactivation of the Epidermal Growth Factor Receptor Is Involved in the Lutropin Receptor-Mediated Down-Regulation of Ovarian Aromatase Expression in Vivo." Molecular Endocrinology 24, no. 3 (March 1, 2010): 552–60. http://dx.doi.org/10.1210/me.2009-0450.

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Abstract Ovarian follicular development and differentiation is characterized by dramatic changes in aromatase (Cyp19a1) expression. In preovulatory follicles, activation of the FSH receptor increases aromatase expression until the surge of LH decreases it. Here we provide in vivo evidence that down-regulation of Cyp19a1 by the LH surge requires efficient signaling through the epidermal growth factor receptor (EGFR). The human chorionic gonadotropin (hCG)-induced down-regulation of Cyp19a1 expression in the two different mouse models with inactivating mutations of the EGFR (wa2 and velvet) is impaired but not abolished. The hCG-induced phosphorylation of ovarian ERK1/2, expression of C/EBPβ, and the phosphorylation of Connexin43 (two downstream targets of ERK1/2 action) are also decreased in these two mouse models. In contrast, disruption of EGFR signaling does not have any affect on the hCG-induced phosphorylation of cAMP response element-binding protein or AKT. This study provides the first in vivo evidence linking the LH receptor, the EGFR, and ERK1/2 as sequential components of a pathway that regulates ovarian Cyp19a1 expression.

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Kuo, Fang-Ting, Kenneth Fan, Ikuko Bentsi-Barnes, Gillian M. Barlow, and Margareta D. Pisarska. "Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell." REPRODUCTION 144, no. 4 (October 2012): 485–94. http://dx.doi.org/10.1530/rep-11-0259.

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The forkhead transcription factor forkhead box L2 (FOXL2) is expressed in granulosa cells of small and medium follicles in the mouse ovary.Foxl2female knockout mice exhibit primordial follicle depletion and primary ovarian failure, but evidence from adult female conditionalFoxl2knockout mice suggests that FOXL2 may also play a significant role in maintenance of ovarian differentiation at stages beyond the primordial follicle and initial wave of folliculogenesis. We previously showed that human FOXL2 functions as a transcriptional repressor of several key genes involved in granulosa cell proliferation and differentiation, including steroidogenic acute regulatory protein (STAR), P450aromatase (CYP19A1(CYP19)), P450scc (CYP11A1(CYP11A)), and cyclin D2 (CCND2). To elucidate the role of mouse FOXL2, we determined its role in transcriptional regulation in Chinese hamster ovary (CHO) cells and then confirmed our findings in mouse granulosa cells. We found that mouse FOXL2 represses the activities of the mouseStar,Cyp19a1,Cyp11a1promoters in CHO cells, but may not repress theCcnd2promoter, and identified the minimal mouseStar,Cyp19a1, andCyp11a1promoter regions responsive to FOXL2 regulation. We then knocked downFoxl2in mouse granulosa cells using siRNA, which resulted in significantly increased expression levels of mouseStar,Cyp19a1, andCyp11a1but notCcnd2. To increaseFoxl2expression levels, we generated a mouseFoxl2lentiviral construct and used it to infect mouse granulosa cells. Following lentiviral infection, the expression levels of mouseStar,Cyp19a1, andCyp11a1, but notCcnd2, decreased significantly. These data confirm that mouse FOXL2 functions as a transcriptional repressor of key granulosa cell genes that influence ovarian development.

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Lunardi, G., L. Del Mastro, M. Serra, P. Driol, C. Boni, F. Cognetti, R. Ponzone, M. Porpiglia, M. Venturini, and P. Pronzato. "Plasma levels of estrone sulfate (ES) in postmenopausal women with breast cancer (BC) during letrozole (L) treatment: Association with single nucleotide polymorphisms (SNPs) of CYP19A1." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 555. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.555.

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555 Background: The CYP19A1 gene encodes aromatase, a key enzyme for estrogen biosynthesis. We investigated the association between four CYP19A1 SNPs, affecting different circulating estrogen levels (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G), and suppression of plasma ES levels induced by 6 weeks (time needed to reach L steady-state concentrations) of L (25 mg/d). Methods: Patients were enrolled into a prospective, italian multi-centre trial (GIM5) testing the correlation of CYP19A1 SNPs with the efficacy of L adjuvant therapy, after 5 years of tamoxifen, in postmenopausal early BC patients. Blood samples for hormone measurements were obtained immediately before starting L (baseline) and following 6 wks of treatment. SNPs were identified from DNA obtained from peripheral blood cells by Hexaprimer Amplification Refractory Mutation System PCR (H-ARMS-PCR). Plasma ES levels were evaluated by Radio Immuno Assay (RIA). Results: SNPs and hormone levels were evaluated in at least 129 patients. SNPs of CYP19A1 were associated with different baseline plasma ES levels. Mean inhibition of aromatase activity induced by L ranges from 71% to 79%, as a function of the SNPs. After 6 weeks of L no difference in ES levels was observed between patients with different SNPs (Table). Conclusions: L therapy induces a higher aromatase suppression in patients with SNPs associated with higher baseline plasma ES levels. The difference in ES levels associated with genetic variation at the CYP19A1 locus disappeared after L therapy. [Table: see text] [Table: see text]

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Liang, Ning, Yinglei Xu, Yimeng Yin, Guidong Yao, Hui Tian, Guishuan Wang, Jie Lian, Yong Wang, and Fei Sun. "Steroidogenic Factor-1 Is Required for TGF-β3-Mediated 17β-Estradiol Synthesis in Mouse Ovarian Granulosa Cells." Endocrinology 152, no. 8 (May 17, 2011): 3213–25. http://dx.doi.org/10.1210/en.2011-0102.

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The TGF-β superfamily members are indicated to play key roles in ovarian follicular development, such as granulosa cell proliferation, estrogens, and progesterone production. However, little is known about the roles of TGF-β3 in follicular development. In this study, we found that TGF-β3 was predominantly expressed in granulosa cells of mouse ovarian follicles, and it significantly promoted 17β-estradiol (E2) release in a dose-dependent manner. The orphan nuclear receptor steroidogenic factor-1 (SF-1) was required in TGF-β3-induced Cyp19a1 (a key rate-limiting enzyme for estrogen biosynthesis) expression and E2 release. Additionally, TGF-β3 enhanced the binding of SF-1 to endogenous ovary-specific Cyp19a1 type II promoter, as evidenced by chromatin immunoprecipitation assays. The enhanced effect of SF-1 by TGF-β3 may be mediated through functional interactions between SF-1 and mothers against decapentaplegic homolog (Smad)3 (a mediator of TGF-β signaling pathway), because disruption of the interaction abolished the synergistic effects of SF-1, Smad3, and TGF-β3 on Cyp19a1 mRNA expression. RNA interference and chromatin immunoprecipitation studies also demonstrated that Smad3 was required for SF-1 binding to Cyp19a1 type II promoter and activation of Cyp19a1. Smad3 thus acts as a point of convergence that involves integration of SF-1 and TGF-β signaling in affecting E2 production. Taken together, our data provide mechanistic insights into the roles of SF-1 in TGF-β3-mediated E2 synthesis. Understanding of potential cross-points between extracellular signals affecting estrogen production will help to discover new therapeutic targets in estrogen-related diseases.

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Baatjes, Karin, Armand Peeters, Micheal McCaul, Maria M. Conradie, Justus Apffelstaedt, Magda Conradie, and Maritha J. Kotze. "CYP19A1 rs10046 Pharmacogenetics in Postmenopausal Breast Cancer Patients Treated with Aromatase Inhibitors: One-year Follow-up." Current Pharmaceutical Design 26, no. 46 (December 30, 2020): 6007–12. http://dx.doi.org/10.2174/1381612826666200908141858.

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Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Conclusions: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

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Villareal, Reina, Angela W. Meisner, Lina Aguirre, Vibhati Kulkarny, Vallabh Shah, Clifford Qualls, Zoneddy Ruiz Dayao, and Melanie Royce. "Association of CYP19A1 gene variants with differences in disease progression in breast cancer patients from different racial/ethnic backgrounds." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1558. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1558.

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1558 Background: Polymorphisms in the aromatase (CYP19A1) gene result in differences in the risk for breast cancer and response to treatment. We hypothesize that allele frequencies in the CYP19A1 gene vary according to race and may result in differences in progression of breast cancer among women from different racial backgrounds. The objectives of this study are: 1) to determine the allele/genotype frequencies in the CYP19A1 gene among women with breast cancer from different racial backgrounds, and, 2) to determine the association between disease progression and CYP19A1 gene variants. Methods: Clinical data and stored DNA from 327 patients participating in the Expanded Breast Cancer Registry (EBCR) program at the University of New Mexico were analyzed. These patients were followed-up for a period of 1 to 6 years. Comprehensive genotyping for CYP19A1 gene single nucleotide polymorphisms (SNPs) was performed using microarray (Illumina). Results: Data from 164 non-Hispanic white and 119 Hispanic women were analyzed. Four SNPs (rs1259269, rs17703883, rs16964211, rs28757101) were associated with differences in genotype/allele frequencies between the 2 racial groups. Furthermore, 3 SNPs (rs4646, rs17647478, and rs6493486) were associated with differences in disease progression. The rare allele (G) for the rs17647478 (G/T) is associated with poor progression compared those without the allele (41.7% vs. 17.1%, p=0.04). Similarly the minor (A) allele for the rs4646 (A/C) and the rs6493486 (A/G) is also associated with a greater chance of worsening disease (23.2% vs. 12.4%, p=0.02 and 23.4% vs. 12.4%, p=0.02, respectively). A significant percentage of women carrying the A allele for both rs4646 and rs6493486 and the T allele for the rs17647478 have more advanced disease at the time of presentation. None of the SNPs analyzed result in racial differences in breast cancer progression. Conclusions: Polymorphisms in the CYP19A1 gene influence overall disease progression in breast cancer patients but have no impact on the racial differences of disease behavior. Women carrying the risk alleles present at a more advanced stage and are also at greater risk of progression.

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Fatkullin, Fatkullin I. F., Gabidullina R. I. Gabidullina, Smirnova G. A. Smirnova, Nukhbala F. R. Nukhbala, Valeeva E. V. Valeeva, Orlova Yu I. Orlova, and Shakirov A. A. Shakirov. "The association between rs2414098 polymorphism of the CYP19A1 gene and the risk of developing endometrial hyperplasia." Akusherstvo i ginekologiia 2_2020 (March 3, 2020): 125–30. http://dx.doi.org/10.18565/aig.2020.2.125-130.

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Uzar, Izabela, Anna Bogacz, Elżbieta Sowińska-Przepiera, Krzysztof Piątek, Filip Przerwa, Marlena Wolek, and Bogusław Czerny. "Association of the CYP19A1 rs700518 Polymorphism with Selected Markers of Bone Metabolism in Women with Hyperandrogenism." Journal of Clinical Medicine 11, no. 12 (June 20, 2022): 3537. http://dx.doi.org/10.3390/jcm11123537.

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Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance of normal estrogen and androgen levels in the blood. Androgens play an important role in the female body because they influence bone mineral density (BMD), body mass composition, muscle mass, mental state, and the regulation of sexual function. The reduced activity of aromatase, due to mutations in the CYP19A1 gene, reduces the estrogen pool in favor of androgens. Clinically, aromatase deficiency causes hyperandrogenism in women. Therefore, the aim of the study was to assess the effect of the CYP19A1 gene polymorphism on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group was comprised of 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, total sRANKL (free and bound RANKL), osteoprotegerin, and total 25-OH Vitamin D. An analysis of the CYP19A1 gene polymorphisms was performed using the real-time PCR method. The GG genotype of the CYP19A1 rs700518 polymorphism turned out to be associated with: FEI (Free Estradiol Index), SHGB concentration, estradiol concentration, and insulin concentration determined in the glucose tolerance test 60’ compared to AG and AA genotypes. Patients with the AG genotype had a higher ratio of android to gynoid fat and a greater content of visceral adipose tissue. Higher visceral tissue content may reduce BMD. In conclusion, the study showed that the CYP19A1 rs700518 polymorphism may be associated with the distribution of adipose tissue in young women with hyperandrogenism. These results suggest that patients with the AG genotype may develop osteoporosis.

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Rodríguez Castaño, Parween, and Pandey. "Bioactivity of Curcumin on the Cytochrome P450 Enzymes of the Steroidogenic Pathway." International Journal of Molecular Sciences 20, no. 18 (September 17, 2019): 4606. http://dx.doi.org/10.3390/ijms20184606.

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Turmeric, a popular ingredient in the cuisine of many Asian countries, comes from the roots of the Curcuma longa and is known for its use in Chinese and Ayurvedic medicine. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have potent wound healing, anti-inflammatory, and anti-carcinogenic activities. While curcuminoids have been studied for many years, not much is known about their effects on steroid metabolism. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the effect of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. When using 10 µg/ml of curcuminoids, both the 17α-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, only a mild reduction in CYP21A2 activity was observed. Furthermore, CYP19A1 activity was also reduced up to ~20% of control when using 1–100 µg/ml of curcuminoids in a dose-dependent manner. Molecular docking studies confirmed that curcumin could dock onto the active sites of CYP17A1, CYP19A1, as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies suggest that curcuminoids may cause inhibition of steroid metabolism, especially at higher dosages. Also, the recent popularity of turmeric powder as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. The molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

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Furuya, Toshiki, and Kuniki Kino. "Regioselective oxidation of indole- and quinolinecarboxylic acids by cytochrome P450 CYP199A2." Applied Microbiology and Biotechnology 85, no. 6 (September 3, 2009): 1861–68. http://dx.doi.org/10.1007/s00253-009-2207-1.

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Goedecke, Julia H., Mehreen Tootla, and Dheshnie Keswell. "Ethnic differences in regional adipose tissue oestrogen receptor gene expression." Endocrine Connections 8, no. 1 (January 2019): 32–38. http://dx.doi.org/10.1530/ec-18-0531.

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Studies have shown ethnic differences in body fat distribution, characterised by greater peripheral and less central fat accumulation in black compared to white South African (SA) women. As sex hormones play an important role in body fat distribution, our study aimed to determine whether differences in body fat distribution between black and white SA women were associated with subcutaneous adipose tissue (SAT) expression of oestrogen receptors (ERA and ERB) and aromatase (CYP19A1). Body fat distribution (DXA and CT) and ERA, ERB and CYP19A1 expression in abdominal and gluteal SAT were measured in 26 black and 22 white SA women. Abdominal SAT ERA and ERB did not differ by ethnicity or BMI. Gluteal ERA was higher (1.08 ± 0.06 vs 0.99 ± 0.05, P < 0.001) and ERB was lower (0.99 ± 0.06 vs 1.10 ± 0.07, P < 0.001) in black vs white SA women. CYP19A1 increased with obesity in all depots (P < 0.001). In both black and white SA women, gluteal ERA was associated with lower central fat mass (FM) and greater gynoid FM (P < 0.05), while the inverse association was shown for CYP19A1 in all depots (P < 0.01). In conclusion, ethnic differences in gluteal ERA expression were associated with differences in body fat distribution previously reported between black and white SA women.

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Ghosh, Debashis, Chinaza Egbuta, Jean E. Kanyo, and TuKiet T. Lam. "Phosphorylation of human placental aromatase CYP19A1." Biochemical Journal 476, no. 21 (November 11, 2019): 3313–31. http://dx.doi.org/10.1042/bcj20190633.

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Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive and central nervous systems. Higher levels of 17β-estradiol (E2) are associated with malignancies and diseases of the breast, ovary and endometrium, while low E2 levels increase the risk for osteoporosis, cardiovascular diseases and cognitive disorders. E2, the transcriptional activator of the estrogen receptors, is also known to be involved in non-genomic signaling as a neurotransmitter/neuromodulator, with recent evidence for rapid estrogen synthesis (RES) within the synaptic terminal. Although regulation of brain aromatase activity by phosphorylation/dephosphorylation has been suggested, it remains obscure in the endocrine and reproductive systems. RES and overabundance of estrogens could stimulate the genomic and non-genomic signaling pathways, and genotoxic effects of estrogen metabolites. Here, by utilizing biochemical, cellular, mass spectrometric, and structural data we unequivocally demonstrate phosphorylation of human placental aromatase and regulation of its activity. We report that human aromatase has multiple phosphorylation sites, some of which are consistently detectable. Phosphorylation of the residue Y361 at the reductase-coupling interface significantly elevates aromatase activity. Other sites include the active site residue S478 and several at the membrane interface. We present the evidence that two histidine residues are phosphorylated. Furthermore, oxidation of two proline residues near the active site may have implications in regulation. Taken together, the results demonstrate that aromatase activity is regulated by phosphorylation and possibly other post-translational modifications. Protein level regulation of aromatase activity not only represents a paradigm shift in estrogen-mediated biology, it could also explain unresolved clinical questions such as aromatase inhibitor resistance.

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Khayeka-Wandabwa, Christopher, Xiaoshuang Ma, Xiaolin Cao, Venkatrao Nunna, Janak L. Pathak, Rita Bernhardt, Pengcheng Cai, and Matthias Bureik. "Plasma membrane localization of CYP4Z1 and CYP19A1 and the detection of anti-CYP19A1 autoantibodies in humans." International Immunopharmacology 73 (August 2019): 64–71. http://dx.doi.org/10.1016/j.intimp.2019.05.003.

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Chen, Xiaowu, Yonghua Zhao, Yudong He, and Jinliang Zhao. "Methylation pattern polymorphism of cyp19a in Nile tilapia and hybrids." Open Life Sciences 13, no. 1 (September 22, 2018): 327–34. http://dx.doi.org/10.1515/biol-2018-0040.

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AbstractSkewed sex development is prevalent in fish hybrids. However, the histological observation and molecular mechanisms remain elusive. In this study, we showed that the interspecific hybrids of the two fish species, Oreochromis niloticus and Oreochromis aureus, had a male ratio of 98.02%. Microscopic examination revealed that the gonads of both male and female hybrids were developmentally retarded. Compared with the ovaries, the testes of both O. niloticus and hybrids showed higher DNA methylation level in two selected regions in the promoter of cyp19a, the gonadal aromatase gene that converts androgens into estrogens, cyp19a showed higher level gene expression in the ovary than in the testis in both O. niloticus and hybrid tilapia. Methylation and gene expression level of cyp19a were negative correlation between the testis and ovary. Gene transcription was suppressed by the methylation of the cyp19a promoter in vitro. While there is no obvious difference of the methylation level in testis or ovary between O. niloticus and hybrids. Thus, the DNA methylation of the promoter of cyp19a may be an essential component of the sex maintenance, but not a determinant of high male ratio and developmental retardation of gonads in tilapia hybrids.

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Houtsma, Daniel, Duveken Fontein, Judith A. M. Wessels, Caroline M. Seynaeve, Cock JH van De Velde, J. W. R. Nortier, Henk-jan Guchelaar, and Hans Gelderblom. "Genetic variation in CYP19A1 and response to exemestane: Survival in early breast cancer in the Dutch TEAM trial." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10518. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10518.

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10518 Background: In patients with endocrine-sensitive breast cancer treated with adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a recurrence and who will benefit from AI’s. Variations in the aromatase gene (CYP19A1) are associated with altered estrogen levels and altered aromatase activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 gene on survival in a prospective cohort of breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and who were treated with five years of exemestane were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. A significant association with worse RFS was found with two SNPs: rs7176005 and rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous variant types respectively. These SNPs, as well as a third SNP, rs6493497, were also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). Conclusions: Germline variations in the CYP19A1 gene are related to a worse outcome in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. The relation between RFS and SNP’s in CYP19A1. [Table: see text]

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Heidarzadehpilehrood, Roozbeh, Maryam Pirhoushiaran, Rasoul Abdollahzadeh, Malina Binti Osman, Maryam Sakinah, Norshariza Nordin, and Habibah Abdul Hamid. "A Review on CYP11A1, CYP17A1, and CYP19A1 Polymorphism Studies: Candidate Susceptibility Genes for Polycystic Ovary Syndrome (PCOS) and Infertility." Genes 13, no. 2 (February 5, 2022): 302. http://dx.doi.org/10.3390/genes13020302.

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Polycystic ovary syndrome is a multifactorial condition associated with reproductive and endocrine organs and might cause infertility and metabolic abnormalities in childbearing age. PCOS seems to be a multifactorial disorder resulting from the combination of several genetic and environmental factors. Little research has been conducted to date on the impact of polymorphisms in infertility. We aim to review the appearance of polymorphisms in females of diverse ethnicities and their effect on infertility in the population with polycystic ovary syndrome. There have been numerous reports of the importance of the steroidogenesis pathway and genetic variants in PCOS pathogenesis. The most important genes that play a role in the aetiology of PCOS are CYP11A1, CYP17A1, and CYP19A1. We evaluated the occurrence of polymorphisms in various ethnicities in the CYP11A1, CYP17A1, and CYP19A1 genes and their efficacy on increasing PCOS risk with infertility. Our findings revealed that polymorphisms in various ethnicities are associated with the risk of PCOS with infertility. Although conflicting results regarding CYP11A1, CYP17A1, and CYP19A1 polymorphisms and their influence on PCOS with infertility have been reported in a small number of papers, the authors feel this may be attributable to the sample size and ethnic composition of the examined populations. In conclusion, our study strongly suggests that the CYP11A1, CYP17A1, and CYP19A1 genes might significantly enhance the probability of developing PCOS with infertility.

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Cao, Shuyan, Leping Ye, Ying Wu, Baiping Mao, Lanlan Chen, Xiudi Wang, Ping Huang, Ying Su, and Ren-Shan Ge. "The Effects of Fungicides on Human 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3." Pharmacology 100, no. 3-4 (2017): 139–47. http://dx.doi.org/10.1159/000475531.

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Placenta secretes a large amount of progesterone and estradiol, which are critical for maintaining pregnancy. In human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) catalyzes pregnenolone to form progesterone, and aromatase (CYP19A1) catalyzes testosterone into estradiol. Fungicides display antifungal activities and are widely used to prevent fungal infections in agricultural plants. These chemicals include azoles, such as tebuconazole (TEB), triadimefon (TRI), and vinclozolin (VCZ) or organotins, such as tributyltin (TBT) and tetrabutyltin (TTBT). Fungicides may disrupt the activities of these 2 enzymes. In the present study, we investigated the effects of these fungicides on steroid production in a human placental cell line JEG-3 and on HSD3B1 and CYP19A1 activities. Of all fungicides tested at 100 µmol/L, only TBT inhibited pregnenolone-mediated progesterone production in JEG-3 cells by over 50%. Except TTBT, all other 4 fungicides inhibited testosterone-mediated estradiol production by over 50%. TBT was a moderate HSD3B1 inhibitor with a half maximal inhibitory concentration (IC50) of 45.60 ± 0.12 µmol/L. When pregnenolone was used to determine the mode of inhibition, TBT was a competitive inhibitor of HSD3B1. The IC50 values of TEB, TRI, VCZ, and TBT for CYP19A1 were 56.84 ± 0.13, 58.73 ± 0.14, 57.42 ± 0.171, and 4.58 ± 0.048 µmol/L, respectively. TEB, TRI, and VCZ were noncompetitive inhibitors of CYP19A1, while TBT was a competitive inhibitor of this enzyme. Therefore, they are endocrine disruptors.

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Journal articles on the topic 'CYP199A4'

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