细胞色素P4502D6遗传多态性与抗疟药研究进展

人类不同种族之间P450基因多态性存在明显的差异,并直接影响约90%临床常用药物在机体内的代谢和转化。英国牛津大学大数据研究所分析提示,目前广泛用于根治间日疟患者的伯氨喹啉药物已经不再适合临床用药,其理由是全球间日疟患者中有超过20%存在CYP2D6基因代谢受损,导致对患者肝脏内潜伏期的休眠子根治无效,同时还有14%的间日疟患者存在葡萄糖6-磷酸脱氢酶（G6PD）缺乏导致溶血,两类患者合计超过间日疟患者总数的34%。由此,改变了过去认为氯喹合并伯氨喹啉根治间日疟患者效果不佳是由于产生抗药性的看法。广西上林县发现非洲输入性间日疟患者采用标准剂量氯喹合并伯氨喹啉多次根治后仍然出现反复发作现象,经检测发现是由于CYP2D6基因代谢受损导致。研究小组尝试采用青蒿素类药物与阿奇霉素配伍进行根治后,至今2年多未见再复发。因此,对间日疟患者经常规根治药物治疗效果不佳时应开展CYP2D6检测。同时研究开发新的间日疟根治药物是目前全球所面临的重大课题。

Advances in genetic polymorphisms of cytochrome P4502D6 and antimalarial drugs

There are obvious differences in P450 gene polymorphisms between the different races of mankind,and directly affects the metabolism and transformation of about 90%of commonly used clinical drugs in the body.The analysis of the Big Data Institute of the University of Oxford in the United Kingdom suggests that the primaquine drug,which is currently widely used to cure vivax malaria patients,is no longer suitable for clinical use.The reason is that more than 20%of patients with Plasmodium vivax worldwide have impaired CYP2 D6 gene metabolism,resulting in ineffective hypnozoite radical cure for patients with incubation period in the liver.At the same time,14%of vivax malaria patients have glucose 6-phosphate dehydrogenase(G6 PD)deficiency,which leads to hemolysis.The two types of patients together exceed 34%of the total number of vivax malaria patients.As a result,the previous view that chloroquine combined with primaquine was not effective in curing vivax malaria patients was mistakenly believed to be due to drug resistance.Shanglin County,Guangxi found that African imported vivax malaria patients still had repeated attacks after repeated eradications with standard doses of chloroquine combined with primaquine,and the test found that the patient was caused by impaired CYP2D6 gene metabolism.After the research team tried to use artemisinin-based drugs and azithromycin for a radical cure,there has been no recurrence for more than 2 years.Therefore,CYP2D6 testing should be carried out for patients with vivax malaria when the effect of conventional radical treatment is not good.At the same time,research and development of new drugs for the eradication of vivax malaria is a major issue facing the world.