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  • Title: Detection of a reactive pyrrole in the hepatic metabolism of the pyrrolizidine alkaloid, monocrotaline.
    Author: Glowaz SL, Michnika M, Huxtable RJ.
    Journal: Toxicol Appl Pharmacol; 1992 Aug; 115(2):168-73. PubMed ID: 1641851.
    Abstract:
    Pyrrolizidine alkaloids such as monocrotaline are bioactivated in the liver, resulting in veno-occlusive disease of the liver, pulmonary arterial hypertension, and right ventricular hypertrophy. We have searched for the formation of a reactive, alkylating pyrrole intermediate in the metabolism of monocrotaline by isolated rat liver microsomes, using the sulfhydryl-containing resin, thiopropyl sepharose 6B, as a trapping agent. Control experiments show that a toxic, chemically reactive, alkylating pyrrole such as dehydromonocrotaline binds covalently to the resin via a thioether bond, but that a less toxic, poorly alkylating pyrrole, such as dehydroretronecine, does not. Isolated hepatic microsomes metabolize monocrotaline to produce a pyrrole that binds to the resin, and that can be detected by means of the Ehrlich color reagent (p-dimethylaminobenzaldehyde). The pyrrole is releasable by silver nitrate treatment, thereby establishing it to be bound via a thioether linkage. In buffered ethanolic silver nitrate the major product is 7-ethoxy-1-hydroxymethyl-6,7-dihydro-5H-pyrrolizine (O7-ethyldehydroretronecine). This establishes that the thioether linkage is at the 7-position. The same product is obtained on release of the resin-bound pyrrole formed from the reaction of dehydromonocrotaline with the resin, thereby establishing the intermediacy of dehydromonocrotaline in the metabolism of monocrotaline.
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