title: Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes.
abstract: Identifying selective inhibitors of cytochrome P450 isoforms is a useful tool in defining the role of individual cytochrome P450s in the metabolism process. In this study, nine chemical inhibitors were selected based on literature data and were examined for their specificity toward cytochrome P450-mediated reactions in human liver microsomes. Furafylline was a potent, mechanism-based inhibitor for CYP1A2-mediated phenacetin O-deethylation. The probes sulfaphenazole (CYP2C9) and quinidine (CYP2D6) selectively inhibited tolbutamide methylhydroxylation and bufuralol 1'-hydroxylation, respectively. Additionally, the CYP2E1-catalyzed chlorzoxazone 6-hydroxylation was significantly inhibited by diethyldithiocarbamate. Of the CYP3A4 inhibitor probes used, troleandomycin proved to be the most specific for testosterone 6 beta-hydroxylation.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: D J
authors.initials: DJ
authors.lastname: Newton
authors.forename: R W
authors.initials: RW
authors.lastname: Wang
authors.forename: A Y
authors.initials: AY
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D013379:Substrate Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D004364:Pharmaceutical Preparations