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Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey Cytochrome P450 2C76, a New Bupropion/Nifedipine Oxidase.
MedLine Citation:
PMID:  25318994     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including cytochrome P450 (P450 or CYP). Most cynomolgus monkey P450s are almost identical (≥90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species difference in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7-ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2C and CYP3A tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolite(s) due to its relatively large substrate cavity.
Authors:
Shinya Hosaka; Norie Murayama; Masahiro Satsukawa; Makiko Shimizu; Shotaro Uehara; Hideki Fujino; Kazuhide Iwasaki; Shunsuke Iwano; Yasuhiro Uno; Hiroshi Yamazaki
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-15
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-16     Completed Date:  -     Revised Date:  2014-10-17    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
The American Society for Pharmacology and Experimental Therapeutics.
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