title: Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine.
abstract: Pyrrolizidine alkaloids (PAs) are probably the most common poisonous plants affecting livestock, wildlife, and humans. The PAs that have been found to be tumorigenic in experimental animals belong to the retronecine-, heliotridine-, and otonecine-type PAs. Our recent mechanistic studies indicated that riddelliine, a tumorigenic retronecine-type PA, induced tumors via a genotoxic mechanism mediated by the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts. The same adducts were formed from clivorine, a tumorigenic otonecine-type PA from metabolism of clivorine by rat liver microsomes in the presence of calf thymus DNA. In this study, we report that metabolism of lasiocarpine, the prototype heliotridine PA, by F344 rat liver microsomes resulted in the formation of DHP. When incubated in the presence of calf thymus DNA, the same DHP-derived DNA adducts were formed. These results suggest that these DHP-derived DNA adducts are potential biomarkers of exposure and tumorigenicity for all types of PAs.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3,900 NCTR Road, HFT0-110, Jefferson, AR 72079, USA.
authors.forename: Qingsu
authors.initials: Q
authors.lastname: Xia
authors.forename: Ming W
authors.initials: MW
authors.lastname: Chou
authors.forename: John A
authors.initials: JA
authors.lastname: Edgar
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Peter P
authors.initials: PP
authors.lastname: Fu
mesh_terms: D000818:Animals; D015415:Biomarkers; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology*; D018736:DNA Adducts; D008297:Male; D008862:Microsomes, Liver; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D018736:DNA Adducts; D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; C007241:dehydroretronecine; C005136:lasiocarpine