{"title":"细胞色素P450氧化还原酶变体A503V有助于他克莫司体外增加CYP3A5活性。","authors":"Yuan Gao, Jingjing Ma","doi":"10.1080/17425255.2022.2112174","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that <i>POR*28</i> contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the <i>POR</i> polymorphism could influence the metabolism of tacrolimus via CYP3A5 <i>in vitro</i>.</p><p><strong>Research design & methods: </strong>A503V is an amino acid sequence variant encoded by <i>POR*28</i>. Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (<i>K</i><sub>m</sub>) and maximum velocity (<i>V</i><sub>max</sub>) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as <i>V</i><sub>max</sub>/<i>K</i><sub>m</sub>.</p><p><strong>Results: </strong>Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels.</p><p><strong>Conclusion: </strong>A503V can affect CYP3A5-catalyzed tacrolimus metabolism <i>in vitro</i>, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":" ","pages":"529-535"},"PeriodicalIF":3.9000,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cytochrome P450 oxidoreductase variant A503V contributes to the increased CYP3A5 activity with tacrolimus <i>in vitro</i>.\",\"authors\":\"Yuan Gao, Jingjing Ma\",\"doi\":\"10.1080/17425255.2022.2112174\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that <i>POR*28</i> contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the <i>POR</i> polymorphism could influence the metabolism of tacrolimus via CYP3A5 <i>in vitro</i>.</p><p><strong>Research design & methods: </strong>A503V is an amino acid sequence variant encoded by <i>POR*28</i>. Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (<i>K</i><sub>m</sub>) and maximum velocity (<i>V</i><sub>max</sub>) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as <i>V</i><sub>max</sub>/<i>K</i><sub>m</sub>.</p><p><strong>Results: </strong>Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels.</p><p><strong>Conclusion: </strong>A503V can affect CYP3A5-catalyzed tacrolimus metabolism <i>in vitro</i>, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.</p>\",\"PeriodicalId\":12250,\"journal\":{\"name\":\"Expert Opinion on Drug Metabolism & Toxicology\",\"volume\":\" \",\"pages\":\"529-535\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2022-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Opinion on Drug Metabolism & Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/17425255.2022.2112174\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/8/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Opinion on Drug Metabolism & Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17425255.2022.2112174","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/8/17 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Cytochrome P450 oxidoreductase variant A503V contributes to the increased CYP3A5 activity with tacrolimus in vitro.
Background: Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that POR*28 contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the POR polymorphism could influence the metabolism of tacrolimus via CYP3A5 in vitro.
Research design & methods: A503V is an amino acid sequence variant encoded by POR*28. Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (Km) and maximum velocity (Vmax) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as Vmax/Km.
Results: Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels.
Conclusion: A503V can affect CYP3A5-catalyzed tacrolimus metabolism in vitro, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.
期刊介绍：
Expert Opinion on Drug Metabolism & Toxicology (ISSN 1742-5255 [print], 1744-7607 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on all aspects of ADME-Tox. Each article is structured to incorporate the author’s own expert opinion on the scope for future development.
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Reviews covering metabolic, pharmacokinetic and toxicological issues relating to specific drugs, drug-drug interactions, drug classes or their use in specific populations; issues relating to enzymes involved in the metabolism, disposition and excretion of drugs; techniques involved in the study of drug metabolism and toxicology; novel technologies for obtaining ADME-Tox data.
Drug Evaluations reviewing the clinical, toxicological and pharmacokinetic data on a particular drug.
The audience consists of scientists and managers in the pharmaceutical industry, pharmacologists, clinical toxicologists and related professionals.
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