title: Species-Specific Differences in the in Vitro Metabolism of Lasiocarpine.
abstract: There are species-related differences in the toxicity of pyrrolizidine alkaloids (PAs) partly attributable to the hepatic metabolism of these alkaloids. In this study, the metabolism of lasiocarpine, a potent hepatotoxic and carcinogenic food contaminant, was examined in vitro with human, pig, rat, mouse, rabbit, and sheep liver microsomes. A total of 12 metabolites (M1-M12) were detected with the human liver microsomes, of which M1, M2, M4, and M6 were unstable in the presence of reduced glutathione (GSH). With the exception of M3 and M8, the formation of all metabolites of lasiocarpine was catalyzed by CYP3A4 in humans. Tandem mass spectra (MS/MS) detected several new metabolites, termed M4-M7; their toxicological significance is unknown. M9 (m/z 398), identified as a demethylation product, was the main metabolite in all species, although the relative dominance of this metabolite was lower in humans. The level of the reactive metabolites, as measured by M1 ((3H-pyrrolizin-7-yl)methanol) and the GSH conjugate, was higher with the liver microsomes of susceptible species (human, pig, rat, and mouse) than with the species (rabbit and sheep) resistant to PA intoxication. In general, in addition to the new metabolites (M4-M7) that could make humans more susceptible to lasiocarpine-induced toxicity, the overall metabolite fingerprint detected with the human liver microsomes differed from that of all other species, yielding high levels of GSH-reactive metabolites.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Muluneh M
authors.initials: MM
authors.lastname: Fashe
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Petsalo
authors.affiliation: Department of Obstetrics and Gynecology, University of Oulu , FI-90220 Oulu, Finland.|Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland , FI-70029 Kuopio, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Räsänen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Pasanen
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D012756:Sheep; D013045:Species Specificity; D013552:Swine; D053719:Tandem Mass Spectrometry
chemical_list: C000599131:(3H-pyrrolizin-7-yl)methanol; D011763:Pyrrolizidine Alkaloids; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione; C005136:lasiocarpine