Takakusa Hideo, Masumoto Hiroshi, Mitsuru Ayako, Okazaki Osamu, Sudo Kenichi
Drug Metabolism Laboratory, Research and Development Division, Shinagawa Research and Development Center, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Drug Metab Dispos. 2008 May;36(5):816-23. doi: 10.1124/dmd.107.018002. Epub 2008 Jan 28.
The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromolecules is considered to be involved in the occurrence of idiosyncratic drug toxicity (IDT). As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2/antioxidant response element system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biological responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine, and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on heme oxygenase 1 (HO-1), which contrasted with the safe drugs; therefore, the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity, including IDT caused by electrophilic reactive metabolites. Moreover, glutathione-depletion and cytochrome P450 (P450)-inhibition experiments have shown that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through P450-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolism-based drug-induced hepatotoxicity and IDT caused by the formation of electrophilic reactive metabolites.
药物代谢活化为亲电反应性代谢物并与细胞大分子共价结合被认为与特异质性药物毒性（IDT）的发生有关。作为对抗氧化和亲电应激的细胞防御系统，已知Ⅱ相酶通过类 Kelch 样 ECH 相关蛋白 1/核因子 E2 相关因子 2/抗氧化反应元件系统被诱导。我们推测，观察暴露于反应性代谢物所引发的生物学反应对于药物性肝毒性和 IDT 的风险评估很重要，然后研究了人肝细胞在暴露于与 IDT 相关的问题药物（如噻氯匹定、双氯芬酸、氯氮平和替尼酸）以及安全药物（如左氧氟沙星和咖啡因）后Ⅱ相酶的 mRNA 诱导谱。根据结果，问题药物对血红素加氧酶 1（HO-1）表现出诱导作用，这与安全药物形成对比；因此，HO-1 mRNA 的诱导似乎与药物毒性的发生相关，包括由亲电反应性代谢物引起的 IDT。此外，谷胱甘肽耗竭和细胞色素 P450（P450）抑制实验表明，观察到的 HO-1 诱导是由问题药物通过 P450 介导的代谢生物活化产生的亲电反应性代谢物触发的。结合我们目前的研究，这表明人肝细胞中 HO-1 的诱导将是基于代谢的药物性肝毒性和由亲电反应性代谢物形成引起的 IDT 发生的良好标志物。
