HYDROXYLATION OF THE ANTIMALARIAL DRUG 58C80 BY CYP2C9 IN HUMAN LIVER-MICROSOMES - COMPARISON WITH MEPHENYTOIN AND TOLBUTAMIDE HYDROXYLATIONS

58C80 4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone] is an experim ental naphthoquinone antimalarial drug which undergoes extensive alkyl hydroxylation to a single t-butylhydroxy metabolite in man in vivo an d also in human liver microsomes, where this is catalysed primarily by a 54 kDa CYP2C9 form of cytochrome P450, P450hB(20-27). Microsomal 58 C80 hydroxylation (58OH) activity showed a marked inter-individual var iation in a bank of 39 individual human livers but did not correlate w ith the immunoquantified levels of either of two microsomal proteins ( 54 and 50 kDa, respectively) recognised by a polyclonal antibody again st CYP2C9 (P450hB(20-27)). Neither 58OH activity nor the concentration s of the CYP2C9-immunorelated proteins showed any relationship with th e 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'-hyd roxylation) activities, while 58C80 inhibited both TBOH and MPOH in hu man liver microsomes non-competitively (K-i = 30 and 175 mu M for TBOH and MPOH, respectively). 58C80 could be a useful model substrate for measuring human CYP2C activity in vitro.