Kwok Hong-Ching, Tse Hei-Tak, Ng Ka-Ki, Wang Shuangshuang, Au Chun-Kit, Cai Zongwei, Chan Wan
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Eastern Institute of Technology Ningbo, Ningbo, Zhejiang 315200, China.
J Agric Food Chem. 2025 Jan 29;73(4):2551-2561. doi: 10.1021/acs.jafc.4c10765. Epub 2025 Jan 14.
Inadvertent exposure to aristolochic acids (AAs) is causing chronic renal disease worldwide, with aristolochic acid I (AA-I) identified as the primary toxic agent. This study employed chemical methods to investigate the mechanisms underlying the nephrotoxicity and carcinogenicity of AA-I. Aristolochic acid II (AA-II), which has a structure similar to that of AA-I, was investigated with the same methods for comparison. Despite their structural similarities, findings from cultured human cells and gut sac experiments showed that AA-I is absorbed more effectively than AA-II (∼3 times greater for AA-I than for AA-II; < 0.001). This increased absorption, along with the previously observed higher activity of reductive activation enzymes for AA-I, results in greater DNA damage and oxidative stress, both of which are key factors in AA-related toxicity. The similar patterns of cell mortality (34.4 ± 2.3% vs 9.7 ± 0.1% for AA-I and AA-II at 80 μM; < 0.0001), DNA adduct formation (∼3 times greater for AA-I than for AA-II; < 0.001), and oxidative stress levels in relation to the concentrations of AA-I and AA-II indicate that the higher absorption rate of AA-I is a significant contributor to its greater toxicity. The toxicity of AA-I was also found to be further enhanced by its (natural) coexistence with AA-II. Since AA-I and AA-II differ only by a methoxy group, future research on reducing risks associated with AA exposure should focus on strategies to lower the absorption of these compounds.
意外接触马兜铃酸（AAs）正在全球范围内引发慢性肾病，其中马兜铃酸I（AA-I）被确定为主要毒性剂。本研究采用化学方法探究AA-I肾毒性和致癌性的潜在机制。采用相同方法对结构与AA-I相似的马兜铃酸II（AA-II）进行研究以作比较。尽管它们结构相似，但来自培养的人类细胞和肠囊实验的结果表明，AA-I的吸收效率高于AA-II（AA-I的吸收量约为AA-II的3倍；<0.001）。这种吸收增加，再加上先前观察到的AA-I还原激活酶活性较高，导致更大的DNA损伤和氧化应激，这两者都是与AA相关毒性的关键因素。细胞死亡率（80μM时AA-I为34.4±2.3%，AA-II为9.7±0.1%；<0.0001）、DNA加合物形成（AA-I约为AA-II的3倍；<0.001）以及与AA-I和AA-II浓度相关的氧化应激水平的相似模式表明，AA-I较高的吸收率是其毒性更大的一个重要因素。还发现AA-I与AA-II（天然）共存会进一步增强其毒性。由于AA-I和AA-II仅相差一个甲氧基，未来关于降低与AA暴露相关风险的研究应侧重于降低这些化合物吸收的策略。
