RT Journal Article
SR Electronic
T1 Microsomal Formation of a Pyrrolic Alcohol Glutathione Conjugate of Clivorine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 181
OP 184
VO 26
IS 2
A1 Ge Lin
A1 Yan-Yan Cui
A1 Edward M. Hawes
YR 1998
UL http://dmd.aspetjournals.org/content/26/2/181.abstract
AB 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