School of Pharmacy (H.Z., X.C.) and Wuya College of Innovation (S.L., Z.Y., Y.P., J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China; and State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China (J.Z.).
School of Pharmacy (H.Z., X.C.) and Wuya College of Innovation (S.L., Z.Y., Y.P., J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China; and State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China (J.Z.)
Drug Metab Dispos. 2018 Apr;46(4):442-450. doi: 10.1124/dmd.117.079327. Epub 2018 Jan 19.
Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of nonsmall cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of cytochrome P450(CYPs) 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent. CYPs 3A4 and 3A5 mainly contributed to the bioactivation of ELT. Microsomal incubation study showed that the ketene intermediate covalently modified the enzyme protein at lysine residues and destroyed the structure of heme. The vinyl and ethyl analogs of ELT showed minor enzyme inhibitory effect (less than 20%), whereas ELT inactivated more than 60% of the enzyme. The present study provided a novel bioactivation pathway of ELT and facilitated the understanding of the mechanisms of ELT-induced mechanism-based enzyme inactivation and liver injury.
厄洛替尼（ELT）是一种酪氨酸激酶抑制剂，临床上广泛用于治疗非小细胞肺癌。不幸的是，在治疗过程中会发生严重的药物性肝损伤和其他不良反应。同时，已有报道称 ELT 是细胞色素 P450（CYPs）3A4 和 3A5 的一种基于机制的失活剂。本研究的目的是鉴定 ELT 的酮烯中间体，并研究 ELT 引起的乙酰化生物活化与酶失活之间的关系。使用 4-溴苯甲胺作为捕获剂，在人微粒体孵育中检测到 ELT 的酮烯中间体。CYPs 3A4 和 3A5 主要参与 ELT 的生物活化。微粒体孵育研究表明，酮烯中间体与赖氨酸残基上的酶蛋白共价结合，并破坏血红素的结构。ELT 的乙烯基和乙基类似物对酶的抑制作用较小（小于 20%），而 ELT 则使超过 60%的酶失活。本研究提供了 ELT 的一种新的生物活化途径，有助于理解 ELT 诱导的基于机制的酶失活和肝损伤的机制。
