TitleAn unprecedented free radical mechanism for the formation of DNA adducts by the carcinogenic N-sulfonated metabolite of aristolochic acids.
Publication TypeJournal Article
Year of Publication2023
AuthorsLi P-L, Huang C-H, Mao L, Li J, Sheng Z-G, Zhu B-Z
JournalFree Radic Biol Med
Date Published2023 Aug 20
KeywordsAristolochic Acids, Carcinogens, Chromatography, High Pressure Liquid, DNA Adducts, Electron Spin Resonance Spectroscopy, Free Radicals

The carcinogenicity of aristolochic acids (AAs) has been attributed mainly to the formation of stable DNA-aristolactam (DNA-AL) adducts by its reactive N-sulfonated metabolite N-sulfonatooxyaristolactam (N-OSO-AL). The most accepted mechanism for such DNA-AL adduct formation is via the postulated but never unequivocally-confirmed aristolactam nitrenium ion. Here we found that both sulfate radical and two ALI-derived radicals (N-centered and C-centered spin isomers) were produced by N-OSO-ALI, which were detected and unequivocally identified by complementary applications of ESR spin-trapping, HPLC-MS coupled with deuterium-exchange methods. Both the formation of the three radical species and DNA-ALI adducts can be significantly inhibited (up to 90%) by several well-known antioxidants, typical radical scavengers, and spin-trapping agents. Taken together, we propose that N-OSO-ALI decomposes mainly via a new N-O bond homolysis rather than the previously proposed heterolysis pathway, yielding reactive sulfate and ALI-derived radicals, which are together and in concert responsible for forming DNA-ALI adducts. This study presents strong and direct evidence for the production of free radical intermediates during N-OSO-ALI decomposition, providing an unprecedented free radical perspective and conceptual breakthrough, which can better explain and understand the molecular mechanism for the formation of DNA-AA adducts, the carcinogenicity of AAs and their potential prevention.

Alternate JournalFree Radic Biol Med
PubMed ID37179032