TY - JOUR T1 - Microsomal Formation of a Pyrrolic Alcohol Glutathione Conjugate of Clivorine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 181 LP - 184 VL - 26 IS - 2 AU - Ge Lin AU - Yan-Yan Cui AU - Edward M. Hawes Y1 - 1998/02/01 UR - http://dmd.aspetjournals.org/content/26/2/181.abstract N2 - The formation of the pyrrolic alcohol glutathione (GSH) conjugates of two different types of pyrrolizidine alkaloids (PAs),i.e. clivorine (an otonecine-type PA) and retrorsine (a retronecine-type PA), was investigated with rat microsomes in the presence of GSH. Two GSH conjugates identified as metabolites of retrorsine were the pyrrolic alcohol conjugated with one [7-GSH-dehydroretronecine (DHP)] or two (7,9-diGSH-DHP) molecules of GSH. diGSH-DHP, the less abundant of the two conjugates, had not been previously identified as a metabolite of PAs. In the case of clivorine, 7-GSH-DHP was identified. This is the first unequivocal identification of a pyrrolic metabolite of an otonecine-type PA. Consequently, this study provides the strongest evidence obtained to date to support the hypothesis, suggested >25 years ago, that the mechanism of hepatotoxicity induced by otonecine-type PAs involves key metabolic steps similar to those for retronecine-type PAs. The American Society for Pharmacology and Experimental Therapeutics ER -