Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
Food Chem Toxicol. 2023 Jul;177:113865. doi: 10.1016/j.fct.2023.113865. Epub 2023 Jun 1.
4-Methylquinoline (4-MQ) is a quinoline derivative widely present in groundwater and soil and has been reported to be genotoxic. The mechanisms of the toxic action remain unknown. This study aimed to elucidate the metabolic activation of 4-MQ and to determine the possible role of reactive metabolites in 4-MQ-induced liver injury in rats. In the present study, a hydroxylation metabolite (M1), a GSH conjugate (M2) and an NAC conjugate (M3) derived from 4-MQ were detected in vitro and in vivo. The structures of the two conjugates were verified by chemical synthesis, mass spectrometry, and nuclear magnetic resonance. CYP3A4 was found to dominate the hydroxylation of 4-MQ. Sulfotransferases also participated in the metabolic activation of 4-MQ. Pretreatment of primary hepatocytes with ketoconazole (KTC) or 2,6-dichloro-4-nitrophenol (DCNP) not only reduced the production of GSH conjugate M2 but also decreased the susceptibility of hepatocytes to the cytotoxicity of 4-MQ. Urinary NAC conjugate M3 was found in rats given 4-MQ, and M3 may be a potential biomarker for 4-MQ exposure.
4- 甲基喹啉（4-MQ）是一种广泛存在于地下水和土壤中的喹啉衍生物，已被报道具有遗传毒性。其毒性作用的机制尚不清楚。本研究旨在阐明 4-MQ 的代谢活化，并确定其在大鼠肝损伤中的可能作用。在本研究中，在体外和体内检测到 4-MQ 的羟化代谢物（M1）、GSH 缀合物（M2）和 NAC 缀合物（M3）。通过化学合成、质谱和核磁共振验证了这两种缀合物的结构。CYP3A4 被发现主导 4-MQ 的羟化。磺基转移酶也参与了 4-MQ 的代谢活化。用酮康唑（KTC）或 2,6-二氯-4-硝基苯酚（DCNP）预处理原代肝细胞，不仅减少了 GSH 缀合物 M2 的产生，而且降低了肝细胞对 4-MQ 细胞毒性的敏感性。在给予 4-MQ 的大鼠尿液中发现了 NAC 缀合物 M3，M3 可能是 4-MQ 暴露的潜在生物标志物。
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