PDF(Pubmed)
Abstract：
Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)-DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.
摘要：
长期以来，马兜铃酸（AAs）由于其肾毒性而被认为是有效的致癌物。马兜铃酸I（AAI）与DNA反应形成共价的马兜铃内酰胺（AL）-DNA加合物，导致随后的A到T变性突变，通常称为AA突变签名。先前的研究推断，AA广泛涉及整个亚洲的肝癌。在这项研究中,我们探讨了AAs暴露是否是中国大陆HBV感染背景下肝癌的主要原因。从3个医学中心随机检索到1256份肝癌样本，并使用精细的生物分析方法检测AAI-DNA加合物。这些样品中的5.10%可被鉴定为AAI阳性暴露。全基因组测序显示，107例肝癌患者中有8.41%表现出显性AA突变特征，表明AAI总体暴露率相对较低。在动物模型中,长期服用AAI几乎不会增加成年小鼠的肝脏肿瘤发生，与其在婴儿小鼠体内的诱导肿瘤作用相反。此外，AAI诱导成年小鼠靶器官中AA-DNA加合物的剂量依赖性积累，检测最多的是肾脏而不是肝脏。一起来看,我们的数据表明,AA暴露不是成年期肝癌的主要威胁.
