title: Hydroxylation of the antimalarial drug 58C80 by CYP2C9 in human liver microsomes: comparison with mephenytoin and tolbutamide hydroxylations.
abstract: 58C80 [2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone] is an experimental naphthoquinone antimalarial drug which undergoes extensive alkyl hydroxylation to a single t-butylhydroxy metabolite in man in vivo and also in human liver microsomes, where this is catalysed primarily by a 54 kDa CYP2C9 form of cytochrome P450, P450hB20-27. Microsomal 58C80 hydroxylation (58OH) activity showed a marked inter-individual variation in a bank of 39 individual human livers but did not correlate with the immunoquantified levels of either of two microsomal proteins (54 and 50 kDa, respectively) recognised by a polyclonal antibody against CYP2C9 (P450hB20-27). Neither 58OH activity nor the concentrations of the CYP2C9-immunorelated proteins showed any relationship with the individuals' age, sex, cigarette smoking habit, alcohol consumption or clinical drug treatment, including long term antiepileptic therapy with phenobarbitone or phenytoin. 58OH activity did not correlate with either TBOH (tolbutamide hydroxylation) or MPOH (S-mephenytoin 4'-hydroxylation) activities, while 58C80 inhibited both TBOH and MPOH in human liver microsomes non-competitively (Ki = 30 and 175 microM for TBOH and MPOH, respectively). 58C80 could be a useful model substrate for measuring human CYP2C activity in vitro.
authors.affiliation: Department of Biomedical Sciences, University of Aberdeen, Marischal College, U.K.
authors.forename: R J
authors.initials: RJ
authors.lastname: Weaver
authors.forename: M
authors.initials: M
authors.lastname: Dickins
authors.forename: M D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000962:Antimalarials / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008617:Mephenytoin / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism*; D039181:Steroid 16-alpha-Hydroxylase; D014044:Tolbutamide / Q000378:metabolism
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D009285:Naphthoquinones; D003577:Cytochrome P-450 Enzyme System; C045010:BW 58C; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D008617:Mephenytoin