Nadin L, Murray M
Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, New South Wales, Australia.
Br J Clin Pharmacol. 1996 Jun;41(6):609-12. doi: 10.1046/j.1365-2125.1996.34919.x.
All-trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukaemia. Other retinoids, including 9-cis- and 13-cis-retinoic acid (9-cis- and 13-cis-RA), are now being evaluated for their therapeutic potential. The elimination of ATRA is partially dependent on cytochrome P450 (P450)-mediated 4-hydroxylation, but the interaction of other retinoids with P450 has not yet been assessed. In the present study 9-cis- and 13-cis-RAs, as well as all-trans-retinol and three isomeric retinals were found to inhibit ATRA 4-hydroxylation in human hepatic microsomes, but the arotinoids acitretin and etretinate were not inhibitors 9-cis- and 13-cis-RA were competitive inhibitors of ATRA 4-hydroxylation (Ki:Km ratios 3.5 +/- 0.8 and 6.3 +/- 0.5, respectively) suggesting that these retinoids are alternate, but inferior, substrates for the P450 enzyme(s) that mediate the activity. The biotransformation of therapeutic retinoids containing the beta-ionone ring system is likely to involve the microsomal ATRA 4-hydroxylase P450.
全反式维甲酸（ATRA）可诱导急性早幼粒细胞白血病患者缓解。目前正在评估其他类视黄醇，包括9-顺式和13-顺式维甲酸（9-顺式和13-顺式RA）的治疗潜力。ATRA的消除部分依赖于细胞色素P450（P450）介导的4-羟基化作用，但其他类视黄醇与P450的相互作用尚未得到评估。在本研究中，发现9-顺式和13-顺式RA以及全反式视黄醇和三种异构视黄醛可抑制人肝微粒体中ATRA的4-羟基化作用，但芳香维甲酸阿维A和依曲替酯不是抑制剂。9-顺式和13-顺式RA是ATRA 4-羟基化作用的竞争性抑制剂（Ki:Km比值分别为3.5±0.8和6.3±0.5），这表明这些类视黄醇是介导该活性的P450酶的替代底物，但效果较差。含有β-紫罗兰酮环系统的治疗性类视黄醇的生物转化可能涉及微粒体ATRA 4-羟化酶P450。
