title: Development of a cell viability assay to assess drug metabolite structure-toxicity relationships.
abstract: Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.
authors.affiliation: Drug Safety Research & Development, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Rana
authors.affiliation: Drug Safety Research & Development, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
authors.affiliation: Compound Safety Prediction, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Sashi
authors.initials: S
authors.lastname: Nadanaciva
authors.affiliation: Medicine Design, Pfizer, 610 Main St., Cambridge, MA 02139, USA. Electronic address: lyn.jones@pfizer.com.
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001553:Benzbromarone / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000378:metabolism / Q000633:toxicity; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D045162:Thiazolidinediones / Q000378:metabolism / Q000633:toxicity; D000077288:Troglitazone
chemical_list: D002839:Chromans; D004364:Pharmaceutical Preparations; D045162:Thiazolidinediones; C004528:benzarone; D001553:Benzbromarone; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D000077288:Troglitazone
keywords: Cytochrome P450; Drug-induced toxicity; Metabolic activation; Reactive metabolite; Structural alerts