Weaver R J, Dickins M, Burke M D
Department of Biomedical Sciences, University of Aberdeen, Marischal College, U.K.
Biochem Pharmacol. 1995 Mar 30;49(7):997-1004. doi: 10.1016/0006-2952(94)00457-w.
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.
58C80 [2-(4-叔丁基环己基)-3-羟基-1,4-萘醌] 是一种实验性萘醌抗疟药物，在人体体内以及人肝微粒体中会广泛发生烷基羟基化反应，生成单一的叔丁基羟基代谢产物，该反应主要由细胞色素P450的54 kDa CYP2C9形式（P450hB20 - 27）催化。在一组39个个体的人肝脏中，微粒体58C80羟基化（58OH）活性表现出显著的个体间差异，但与针对CYP2C9（P450hB20 - 27）的多克隆抗体识别的两种微粒体蛋白（分别为54 kDa和50 kDa）的免疫定量水平均无相关性。58OH活性以及CYP2C9免疫相关蛋白的浓度均与个体的年龄、性别、吸烟习惯、饮酒情况或临床药物治疗（包括长期使用苯巴比妥或苯妥英进行抗癫痫治疗）无关。58OH活性与TBOH（甲苯磺丁脲羟基化）或MPOH（S-美芬妥因4'-羟基化）活性均无相关性，而58C80在人肝微粒体中对TBOH和MPOH均有非竞争性抑制作用（TBOH和MPOH的Ki分别为30和175 microM）。58C80可能是一种用于体外测量人CYP2C活性的有用模型底物。
