Yun C H, Lee H S, Lee H, Rho J K, Jeong H G, Guengerich F P
Department of Biochemistry, Pai-Chai University, Seo-ku, Taejon, South Korea.
Drug Metab Dispos. 1995 Feb;23(2):285-9.
The oxidative metabolism of losartan (DuP 753), a novel angiotensin II receptor antagonist, by human liver microsomes and purified cytochrome P450 (P450) enzymes, was studied. The primary route of metabolism of losartan is by oxidation of the C5-hydroxymethyl to the carboxylic acid (EXP3174), which is an active metabolite of losartan. When microsomes prepared from different human liver samples were compared, EXP3174 formation activity was well correlated (r2 = 0.93) with nifedipine oxidation (a marker of P4503A4), but not with markers for other human liver P450s. Microsomal oxidation of losartan to EXP3174 was markedly inhibited by gestodene and ketoconazole, selective inhibitors of P4503A enzymes, but not by any of several other P450 inhibitors. Antibodies raised against P4503A4 could inhibit most of the oxidation of losartan to EXP3174 in a microsomal sample having high catalytic activity, but antibodies recognizing other P450s had no effect. The oxidation of losartan to EXP3174 was catalyzed by purified human liver microsomal P4503A4 and by purified bacterial recombinant P4503A4. These results provide evidence that P4503A4 (and possibly other P4503A enzymes) play a major role in the formation of an active metabolite EXP3174.
研究了新型血管紧张素II受体拮抗剂氯沙坦（DuP 753）在人肝微粒体和纯化细胞色素P450（P450）酶中的氧化代谢。氯沙坦的主要代谢途径是将C5-羟甲基氧化为羧酸（EXP3174），这是氯沙坦的一种活性代谢产物。比较不同人肝样本制备的微粒体时，EXP3174形成活性与硝苯地平氧化（P4503A4的标志物）具有良好的相关性（r2 = 0.93），但与其他人肝P450的标志物无关。P4503A酶的选择性抑制剂孕二烯酮和酮康唑可显著抑制氯沙坦微粒体氧化为EXP3174，但其他几种P450抑制剂则无此作用。针对P4503A4产生的抗体可抑制具有高催化活性的微粒体样本中氯沙坦大部分氧化为EXP3174，但识别其他P450的抗体则无作用。纯化的人肝微粒体P4503A4和纯化的细菌重组P4503A4可催化氯沙坦氧化为EXP3174。这些结果证明P4503A4（可能还有其他P4503A酶）在活性代谢产物EXP3174的形成中起主要作用。
