Shou M, Martinet M, Korzekwa K R, Krausz K W, Gonzalez F J, Gelboin H V
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Pharmacogenetics. 1998 Oct;8(5):391-401. doi: 10.1097/00008571-199810000-00004.
Taxotere, a promising anticancer agent, is metabolized almost exclusively in liver and excreted from bile in all species. To determine which cytochrome P450 is involved in taxotere biotransformation, 11 cDNA-expressed human cytochrome P450s were examined for their activity in the metabolism of taxotere and its derivatives. Of all P450s, cytochrome P450 3A4 and 3A5 were the most active for the oxidation of taxotere to the primary metabolite RPR104952 and for subsequent oxidation of RPR104952 to RPR111059 and RPR111026. RP70617, an epimer of taxotere was also metabolized by both P450 3A enzymes to form metabolite XII. The activity of 3A4/5 enzymes for these substrates was 4-50-fold greater than the other P450s examined. The Kms of 3A4 and 3A5 for taxotere were 0.91 and 9.28 microM, and Vmax for the formation of RPR104952 were 1.17 and 1.36 m(-1), respectively. The contribution of the 3A enzyme complex to the metabolism of taxotere in human livers from 21 individuals was assessed with the inhibitory monoclonal antibody and ranged from 64-93%. The primary oxidative metabolism of taxotere by human liver microsomes was well correlated with 3A4-dependent reactions for testosterone 6beta-hydroxylation (r2 = 0.84), taxol aromatic hydroxylation (r2 = 0.67) and aflatoxin B1 3alpha-hydroxylation (r2 = 0.63); whereas a poor correlation was found for reactions specifically catalysed by other P450s (all r2 < or =O.17). The extent of taxotere metabolism also closely correlated with levels of 3A4 enzyme in human livers quantified with immunoblot monoclonal antibody (r2 = 0.61). These results demonstrate that the P450 3A4 and 3A5 enzymes are major determinants in taxotere oxidation and suggest that care must be taken when administering this drug with other drugs that are also substrates for these enzymes.
泰索帝是一种很有前景的抗癌药物，在所有物种中几乎都仅在肝脏中代谢，并通过胆汁排泄。为了确定哪种细胞色素P450参与泰索帝的生物转化，检测了11种cDNA表达的人细胞色素P450对泰索帝及其衍生物代谢的活性。在所有的P450中，细胞色素P450 3A4和3A5对将泰索帝氧化为主要代谢产物RPR104952以及随后将RPR104952氧化为RPR111059和RPR111026的活性最高。泰索帝的差向异构体RP70617也被两种P450 3A酶代谢形成代谢产物XII。3A4/5酶对这些底物的活性比对所检测的其他P450高4至50倍。3A4和3A5对泰索帝的Km分别为0.91和9.28 microM，形成RPR104952的Vmax分别为1.17和1.36 m(-1)。用抑制性单克隆抗体评估了3A酶复合物对21名个体人肝脏中泰索帝代谢的贡献，范围为64%至93%。人肝微粒体对泰索帝的主要氧化代谢与睾酮6β-羟基化的3A4依赖性反应（r2 = 0.84）、紫杉醇芳香族羟基化（r2 = 0.67）和平flat毒素B1 3α-羟基化（r2 = 0.63）密切相关；而与其他P450特异性催化的反应相关性较差（所有r2≤0.17）。泰索帝的代谢程度也与用免疫印迹单克隆抗体定量的人肝脏中3A4酶水平密切相关（r2 = 0.61）。这些结果表明，P450 3A4和3A5酶是泰索帝氧化的主要决定因素，并表明在将该药物与也是这些酶底物的其他药物合用时必须谨慎。
