Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants

IF 1.7 4区医学 Q3 PHARMACOLOGY & PHARMACY Biopharmaceutics & Drug Disposition Pub Date : 2023-10-10 DOI:10.1002/bdd.2378

Shiori Takeji, Mai Okada, Shu Hayashi, Kengo Kanamaru, Yuichi Uno, Hiromasa Imaishi, Tomohide Uno

{"title":"Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants","authors":"Shiori Takeji, Mai Okada, Shu Hayashi, Kengo Kanamaru, Yuichi Uno, Hiromasa Imaishi, Tomohide Uno","doi":"10.1002/bdd.2378","DOIUrl":null,"url":null,"abstract":"<p>CYP2C19 is a member of the human microsomal cytochrome P450 (CYP). Significant variation in CYP2C19 levels and activity can be attributed to polymorphisms in this gene. Wildtype CYP2C19 and 13 mutants (CYP2C19.1B, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.11, CYP2C19.13, CYP2C19.16, CYP2C19.19, CYP2C19.23, CYP2C19.30, and CYP2C19.33) were coexpressed with NADPH-cytochrome P450 reductase in <i>Escherichia coli</i>. Hydroxylase activity toward testosterone and progesterone was also examined. Ten CYP2C19 variants showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra. CYP2C19.11 and CYP2C19.23 showed higher testosterone 11α, 16α-/17- and progesterone 6β-,21-,16α-/17α-hydroxylase activities than CYP2C19.1B. CYP2C19.6, CYP2C19.16, CYP2C19.19, and CYP2C19.30 showed lower activity than CYP2C19.1B. CYP2C19.9, CYP2C19.10. CYP2C19.13, and CYP2C19.33 showed different hydroxylation activities than CYP2C19.1B. These results indicated that CYP2C19 variants have very different substrate specificities for testosterone and progesterone.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 6","pages":"420-430"},"PeriodicalIF":1.7000,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biopharmaceutics & Drug Disposition","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bdd.2378","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

CYP2C19 is a member of the human microsomal cytochrome P450 (CYP). Significant variation in CYP2C19 levels and activity can be attributed to polymorphisms in this gene. Wildtype CYP2C19 and 13 mutants (CYP2C19.1B, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.11, CYP2C19.13, CYP2C19.16, CYP2C19.19, CYP2C19.23, CYP2C19.30, and CYP2C19.33) were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. Hydroxylase activity toward testosterone and progesterone was also examined. Ten CYP2C19 variants showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra. CYP2C19.11 and CYP2C19.23 showed higher testosterone 11α, 16α-/17- and progesterone 6β-,21-,16α-/17α-hydroxylase activities than CYP2C19.1B. CYP2C19.6, CYP2C19.16, CYP2C19.19, and CYP2C19.30 showed lower activity than CYP2C19.1B. CYP2C19.9, CYP2C19.10. CYP2C19.13, and CYP2C19.33 showed different hydroxylation activities than CYP2C19.1B. These results indicated that CYP2C19 variants have very different substrate specificities for testosterone and progesterone.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

细胞色素P450 2C19等位基因变异体对睾酮和孕酮的代谢。

CYP2C19是人微粒体细胞色素P450（CYP）的成员。CYP2C19水平和活性的显著变化可归因于该基因的多态性。野生型CYP2C19和13个突变体（CYP2C19.1B、CYP2C19.5A、CYP2C1955B、CYP2C19.6、CYP2C19.8、CYP2C19.7、CYP2C19.10、CYP2C19.11、CYP2C1913、CYP2C19.1 6、CYP2C19.19、CYP2C19 23、CYP2C19.30和CYP2C19.33）在大肠杆菌中与NADPH细胞色素P450还原酶共表达。还检测了对睾酮和孕酮的羟化酶活性。10个CYP2C19变体在减少的CO差异光谱中显示P450的典型Soret峰（450nm）。CYP2C19.11和CYP2C19.23显示出比CYP2C19.1B更高的睾酮11α，16α-/17和孕酮6β，21-，16α-1/17α-羟化酶活性。CYP2C19.13和CYP2C19.33显示出与CYP2C19.1B不同的羟基化活性。这些结果表明CYP2C19变体对睾酮和孕酮具有非常不同的底物特异性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Biopharmaceutics & Drug Disposition 医学-药学

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods