Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Chem Res Toxicol. 2023 Feb 20;36(2):322-329. doi: 10.1021/acs.chemrestox.2c00415. Epub 2023 Feb 9.
Prolonged exposure to aristolochic acid (AA) through AA-containing herbal medicines or AA-tainted food is putting a large portion of the global population at risk of developing renal fibrosis and tumors of the upper urinary tract. In an effort to better understand the organotropic property of AA, we studied the cytotoxicity, absorption, oxidative-stress inducing potential, and DNA adduct formation capability of aristolactam I (ALI), one of the major urinary metabolites of aristolochic acid I (AAI) in human cells. Despite ALI having a slightly lower cytotoxicity than that of AAI, the analysis revealed, for the first time, that ALI is bioaccumulated 900 times more than that of AAI inside cultured kidney cells. Furthermore, ALI induced a significantly larger glutathione depletion than that of AAI in the exposed cells. Together with the formation of ALI-DNA adduct at a reasonably high abundance, results of this study unmasked a previously disregarded causative role of ALI in the organotropic tumor-targeting property of AA.
长期摄入含有马兜铃酸的草药或受马兜铃酸污染的食物，使全球很大一部分人面临罹患肾纤维化和上尿路肿瘤的风险。为了更好地了解马兜铃酸的器官靶向特性，我们研究了马兜铃内酰胺 I（ALI）的细胞毒性、吸收、诱导氧化应激潜力和 DNA 加合物形成能力，ALI 是马兜铃酸 I（AAI）在人细胞中的主要尿代谢物之一。尽管 ALI 的细胞毒性略低于 AAI，但分析首次表明，在培养的肾细胞中，ALI 的生物累积量是 AAI 的 900 倍。此外，ALI 在暴露的细胞中引起的谷胱甘肽耗竭比 AAI 更为显著。与在相当高丰度下形成 ALI-DNA 加合物一起，这项研究的结果揭示了 ALI 在 AA 的器官靶向肿瘤靶向特性中以前被忽视的因果作用。
