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.

吡咯里西啶生物碱 (PA) 是具有肝毒性、遗传毒性和致癌性的植物化学物质。代谢活化后，PA 产生脱氢吡咯里西啶生物碱（脱氢-PA）作为反应性主要吡咯代谢物。Dehydro-PAs 不稳定，容易水解为 (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-吡咯嗪 (DHP)。脱氢-PA 和 DHP 都能够与细胞 DNA 和蛋白质结合，形成 DHP-DNA 和 DHP-蛋白质加合物，导致致瘤性和细胞毒性。我们最近确定脱氢-PAs 与谷胱甘肽和半胱氨酸的反应分别产生 7-谷胱甘肽-DHP (7-GS-DHP) 和 7-半胱氨酸-DHP，它们也可以与 DNA 结合产生 DHP-DNA 加合物。在这项研究中，我们确定了谷胱甘肽和半胱氨酸对诱导肝细胞毒性和在用瑞德林和野百合碱培养的原代肝细胞中形成 DHP-DNA 加合物的影响。我们发现谷胱甘肽和半胱氨酸都可以显着降低肝毒性，而 DHP-DNA 加合物形成的水平受到轻微影响。