Firm Evidence for the Formation of a Pyrrolic Metabolite of an Otonecine-Type Pyrrolizidine Alkaloid
Abstract
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.
Footnotes
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Send reprint requests to: Dr. Ge Lin, Department of Pharmacology, The Chinese University of Hong Kong, Shatin, Hong Kong.
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This work was supported by the Research Grant Council of Hong Kong (Earmarked Research Grant CUHK 415/95M).
- Abbreviations used are::
- PA
- pyrrolizidine alkaloid
- DHP
- dehydroretronecine [7(R)-hydroxy-1-hydroxymethyl-6,7-dihydro-5H-pyrrolizidine]
- GSH
- glutathione
- Received June 30, 1997.
- Accepted October 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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