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  • Title: Effects of glutathione and cysteine on pyrrolizidine alkaloid-induced hepatotoxicity and DNA adduct formation in rat primary hepatocytes.
    Author: He X, Xia Q, Shi Q, Fu PP.
    Journal: J Environ Sci Health C Toxicol Carcinog; 2020; 38(2):109-123. PubMed ID: 32500832.
    Abstract:
    Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic phytochemicals. Upon metabolic activation, PAs produce dehydropyrrolizidine alkaloids (dehydro-PAs) as reactive primary pyrrolic metabolites. Dehydro-PAs are unstable, facilely hydrolyzed to (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP). Both dehydro-PAs and DHP are capable of binding to cellular DNA and proteins to form DHP-DNA and DHP-protein adducts leading to tumorigenicity and cytotoxicity. We recently determined that the reaction of dehydro-PAs with glutathione and cysteine generated 7-glutathione-DHP (7-GS-DHP) and 7-cysteine-DHP, respectively which can also bind to DNA to produce DHP-DNA adducts. In this study, we determined the effects of glutathione and cysteine on the induction of hepatocytotoxicity and the formation of DHP-DNA adducts in primary hepatocytes cultured with riddelliine and monocrotaline. We found that both glutathione and cysteine can drastically reduce hepatotoxicity while the levels of DHP-DNA adduct formation are slightly affected.
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