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Identifying Cysteine, N‑Acetylcysteine, and Glutathione Conjugates as Novel Metabolites of Aristolochic Acid I: Emergence of a New Detoxification Pathway
journal contribution
posted on 2020-02-24, 20:43 authored by Jiayin Zhang, Chi-Kong Chan, Yat-Hing Ham, Wan ChanThere
is accumulating evidence that Balkan endemic nephropathy
(BEN) is an environmental disease caused by aristolochic acids (AAs)
released from the decomposition of Aristolochia clematitis L., an AA-containing weed that grows abundantly in the Balkan Peninsula.
AA exposure has also been associated with carcinoma development in
the upper urinary tract of some patients suffering from BEN. It is
believed that an aristolactam-nitrenium ion intermediate with a delocalized
positive charge produced in the hepatic metabolism of AAs binds to
DNA and the resulting DNA adduct is responsible for initiating the
carcinoma development process. In this study, we demonstrated for
the first time that the aristolactam-nitrenium ion intermediate will
also react with endogenous aminothiols, for example, cysteine, N-acetylcysteine, and glutathione in vitro, and in rats, producing phase II-conjugated metabolites in a dosage-dependent
manner. It is highly possible that this conjugation process consumes
and ultimately deactivates this carcinogenic intermediate and acts
as an important, but previously unreported, detoxification mechanism
of AAs. Results also showed AAs, phase I metabolites, and the aminothiol-conjugated
metabolites are rapidly eliminated from AA-exposed rats. Furthermore,
we found evidence that AA exposure induced oxidative stress in rats,
as indicated by the glutathione depletion in rat serum samples.