MICROSOMAL FORMATION OF A PYRROLIC ALCOHOL GLUTATHIONE CONJUGATE OF CLIVORINE FIRM EVIDENCE FOR THE FORMATION OF A PYRROLIC METABOLITE OF AN OTONECINE-TYPE PYRROLIZIDINE ALKALOID

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 inve stigated with rat microsomes in the presence of GSH. Two GSH conjugate s identified as metabolites of retrorsine were the pyrrolic alcohol co njugated with one [7-GSH-dehydroretronecine (DHP)] or two (7,9-diGSH-D HP) molecules of GSH. diGSH-DHP, the less abundant of the two conjugat es, had not been previously identified as a metabolite of PAs. In the case of clivorine, 7-GSH-DHP was identified. This is the first unequiv ocal identification of a pyrrolic metabolite of an otonecine-type PA. Consequently, this study provides the strongest evidence obtained to d ate to support the hypothesis, suggested >25 years ago, that the mecha nism of hepatotoxicity induced by otonecine-type PAs involves key meta bolic steps similar to those for retronecine-type PAs.