Biliary excretion of novel pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline

Abstract

W. M. Lafranconi, S. Ohkuma and R. J. Huxtable. Biliary excretion of novel pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline. Toxicon 23, 983–992, 1985. — Perfusion of the pyrrolizidine alkaloid, monocrotaline, through the isolated rat liver resulted in the appearance of Ehrlich-positive metabolites in both the perfusate and bile. Livers from male rats released greater quantities of metabolite into both bile and perfusate. Metabolite release was stimulated by pretreatment with phenobarbital. Livers of phenobarbital-pretreated male rats perfused with 300 μM monocrotaline produced biliary metabolite concentrations in excess of 5 mM. Metabolite release was inhibited by anoxic perfusion; low temperature and pretreatment with SKF-525A. Above 150 μM monocrotaline, bile became the predominant route of excretion. On perfusion through the isolated lung of the rat, bile and perfusate metabolites were equally effective in inhibiting serotonin transport. A single Ehrlich-positive peak was obtained on silica gel column chromatography of bile containing metabolite. Mass spectrometry revealed the major component of this peak to have a molecular weight of 281, indicating a novel pyrrole metabolite in which the esterifying acid present in monocrotaline, monocrotalic acid, had been partially degraded. This compound mimics the pneumotoxic action of monocrotaline giver, in vivo, and its availability should prove a valuable tool in the elucidation of the mechanism of pyrrolizidine toxicity.