Sex-specific toxicity targets of aristolochic acids: nephrotoxicity in males, hepatotoxicity in females

Aristolochic acids (AAs), derived from Aristolochia herbs, are well-known nephrotoxins, and emerging evidence suggests their potential role in the development of liver cancers. However, the specific organs most affected by AAs, particularly in relation to liver cancer, remain unclear. Considering the known sex differences in enzyme activities, we hypothesized that variations in AA metabolism may contribute to the kidney and liver toxicity associated with these compounds. Our analysis of DNA adducts in the kidneys and livers of mice treated with aristolochic acid I (AA-I) revealed that male mice exhibited over 2.5 times higher levels of DNA adducts in their kidney DNA compared to female mice. Conversely, female mice showed 1.5 times higher adduct levels in their liver DNA than their male counterparts. These findings indicate that AA exposure presents a sex-specific disease risk, with males being at greater risk for kidney disease and females for liver disease. Additionally, we observed similar concentration patterns of the metabolite aristolactam I (AL-I) and the activity of NQO1 enzymes in the respective organs. Further in vitro studies, involving the incubation of AA-I with liver and kidney homogenates, demonstrated significant differences in AL-I concentrations, mirroring the trends observed in the AA-DNA adduct and AL-I analyses of AA-I-exposed mice. Collectively, these results underscore the importance of sex differences in the enzymatic activity responsible for the metabolic activation of AAs, which is critical for understanding the differential nephrotoxic and hepatotoxic effects associated with these compounds.