Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China.
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.
J Biochem Mol Toxicol. 2019 Sep;33(9):e22366. doi: 10.1002/jbt.22366. Epub 2019 Jul 23.
Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL-induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration-time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL-induced liver injury.
秋水仙碱（COL）是存在于百合科秋水仙属植物中的一种生物碱。它已广泛用于治疗多种疾病，如痛风、家族性地中海热和肿瘤。然而，COL 的不良反应是其安全使用的障碍。本研究探讨了代谢去甲基化在 COL 诱导肝毒性中的作用。我们发现，CYP3A 的抑制增加了小鼠对 COL 肝毒性的易感性，而 CYP3A 的诱导降低了动物对肝毒性的易感性。毒代动力学研究表明，酮康唑预处理导致 COL 的浓度-时间曲线下面积升高。发现 COL 的三种去甲基化代谢物的肝毒性低于母体化合物。似乎亲电去甲基化代谢物的形成与 COL 诱导的肝损伤的发展无关。
