人类白细胞抗原基因的遗传变异与药物不良反应的关系

Progress in study on the association between HLA genetic variation and adverse drug reactions

人类主要组织相容性复合体编码的人类白细胞抗原(human leukocyte antigen,HLA)分子是一组高度保守且与抗原识别有关的细胞表面蛋白。HLA基因具有高度基因多态性,构成免疫个体差异的基础,与药物不良反应关系密切,如HLA-A*31:01和HLA-B*15:02基因与卡马西平诱导的严重皮肤不良反应有关,HLA-B*57:01基因与阿巴卡韦诱导的药物超敏反应综合征以及氟氯西林和帕唑帕尼诱导的药物性肝损伤有关;HLA-B*35:01基因可作为中药何首乌肝损伤的潜在分子标志物。小分子药物与HLA分子和T细胞受体相互作用的机制尚不清楚,现有的4种认可度较高的机制假说分别为半抗原学说、药理相互作用学说、改变肽库学说和改变T细胞受体学说。

The human leukocyte antigen(HLA)molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins,which are related to antigen recognition.HLA genes display a high degree of genetic polymorphism,which is the basis of individual differences in immunity.Specific HLA genotypes have been highly associated with typical adverse drug reactions.HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions,HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury,while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury.It is not clear how small drug molecules to interact with HLA molecules and T cell receptors(TCR).There are four mechanistic hypotheses,including the hapten/prohapten theory,the pharmacological interaction concept,the altered peptide repertoire model,and the altered TCR repertoire model.