香豆素类化合物毒理研究及安全性思考

Toxicological research and safety consideration of coumarins

香豆素是自然界重要的一类有机天然化合物,广泛存在于多种植物、微生物中。香豆素类化合物具有抗肿瘤、抗HIV、抗菌、抗炎、抗氧化、抗凝血等多种生物活性和广泛的临床用途,但在啮齿类动物中存在明显的毒性作用。研究发现香豆素类化合物的毒性在不同动物及其不同器官中具有明显的差异,高剂量口服给药更容易产生毒性反应。该文通过对近60年来国内外文献的研究分析,重点综述香豆素类化合物诱导的肝毒性、肺毒性等,并对其可能的机制进行探讨,发现香豆素类化合物的毒性具有代谢差异和物种差异,大鼠的肝脏和小鼠的肺更容易受到香豆素影响,且毒性反应多发生于香豆素体内代谢的第2种代谢途径。以此提出安全性思考,评价香豆素对人体的影响,发现香豆素在正常暴露水平下,人体不太可能产生肝毒性;并且提出在评估香豆素毒性时应谨慎考虑因模型动物体内代谢方式的不同而导致的物种差异。以期为香豆素类化合物临床研究与合理使用提供借鉴,提高对香豆素类药物的合理使用。

Coumarin is an important class of natural organic compounds,which widely exists in a variety of plants and microorganisms.Coumarins have many biological activities and wide clinical applications,such as anti-tumor,anti-HIV,anti-bacterial,anti-inflammatory,anti-oxidation,anti-coagulation,but they have obvious toxic effects in rodents.It was found that the toxicity of coumarins in different animals and organs was significantly different,and high dose oral administration was more likely to produce toxic reactions.Based on the research and analysis of domestic and foreign literatures in recent 60 years,this paper mainly summarized the hepatotoxicity and pulmonary toxicity induced by coumarins,and probed into their possible mechanisms.It was found that the toxicity of coumarins had metabolic differences and species differences.The liver of rats and lungs of mice were more susceptible to coumarins.Toxic reactions occurred mainly in the second metabolic pathway of coumarin metabolism in vivo.In order to put forward safety considerations and evaluate the impact of coumarin on human body,it was found that coumarin is unlikely to produce hepatotoxicity at normal exposure level.It was also suggested that species differences due to different metabolic patterns in model animals should be carefully considered when assessing coumarin toxicity,in order to provide reference for clinical research and rational use of coumarins and improve the rational use of coumarins.