7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids. (2nd January 2016)

• Record Type: Journal Article
• Authors: He, Xiaobo; Xia, Qingsu; Ma, Liang; Fu, Peter P.
• Is Part Of: Journal of environmental science and health. Volume 34:Number 1(2016)
• Page Start: 57
• Page End: 76
• Publication Date: 2016-01-02
• Subjects: Pyrrolizidine alkaloid -- metabolic activation -- 7-cysteine-DHP adducts -- DNA adduct formation; Carcinogenesis -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmentally induced diseases -- Periodicals; Environmental Health -- periodicals; Carcinogens, Environmental -- periodicals; Hazardous Substances -- periodicals; 616.994071
• DOI: 10.1080/10590501.2015.1135593
• Languages: English
• ISSNs: 1059-0501

Abstract

ABSTRACT: Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (±)-6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.