title: 7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids.
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.
authors.affiliation: a National Center for Toxicological Research, US Food and Drug Administration , Jefferson , Arkansas , USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: He
authors.affiliation: a National Center for Toxicological Research, US Food and Drug Administration , Jefferson , Arkansas , USA.
authors.forename: Qingsu
authors.initials: Q
authors.lastname: Xia
authors.affiliation: a National Center for Toxicological Research, US Food and Drug Administration , Jefferson , Arkansas , USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: a National Center for Toxicological Research, US Food and Drug Administration , Jefferson , Arkansas , USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Fu
mesh_terms: D000818:Animals; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D016686:Monocrotaline / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism* / Q000493:pharmacokinetics; D011916:Rats, Inbred F344; D053719:Tandem Mass Spectrometry
chemical_list: D018736:DNA Adducts; D011763:Pyrrolizidine Alkaloids; C013672:riddelliine; D016686:Monocrotaline; D004247:DNA; C427203:calf thymus DNA; D005978:Glutathione; D003545:Cysteine; C007241:dehydroretronecine
keywords: 7-cysteine-DHP adducts; DNA adduct formation; Pyrrolizidine alkaloid; metabolic activation