THE COMPARATIVE METABOLISM OF THE 4 PYRROLIZIDINE ALKALOIDS, SENECIPHYLLINE, RETRORSINE, MONOCROTALINE, AND TRICHODESMINE IN THE ISOLATED, PERFUSED-RAT-LIVER

Despite their similarity in structure, pyrrolizidine alkaloids (PAs) v ary in their LD50s and in the organs in which toxicity is expressed. W e have examined whether there are differences in the metabolism of cer tain PAs that are associated with these quantitative and qualitative d ifferences in toxicity. Isolated rat livers were perfused with one of four PAs (seneciphylline, retrorsine, monocrotaline, and trichodesmine ) at 0.5 mM for 1 hr, and the pyrrolic metabolites determined that wer e released into perfusate and bile or bound in the liver. The proporti on of the PA removed by the liver varied from 93% for retrorsine to 55 % for trichodesmine. However, trichodesmine-perfused livers released t he greatest amount of the dehydroalkaloid into the perfusate. These re active pyrrolic metabolites appear to be largely responsible for the t oxicity of PAs. Over the course of a l-hr perfusion, dehydroalkaloid r elease varied fourfold among the PAs examined. Seneciphylline and retr orsine significantly increased bile flow. Highest concentrations of PA s in bile were achieved at 30-40 min perfusion. Conversion of dehydroa lkaloid to the conjugate 7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H - pyrrolizine (GSDHP) is a detoxification reaction. GSDHP release into bile varied from 80 nmol/g liver for trichodesmine to 880 nmol/g for retrorsine. Release of the less toxic hydrolytic product of dehydroalk aloids, -dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine, was also de termined. Bound pyrroles in liver are probably an indication of heptat oxicity. At the end of perfusion these varied from 55 nmol/g for monoc rotaline to 195 nmol/g for retrorsine. The chemical form of the bound pyrroles is a 7-thioether conjugate of 6,7-dihydro-1-hydroxymethyl-5H- pyrrolizine. No 7,9-dithio conjugate was detected, indicating that onl y monoalkylation has been found. These differences in metabolic patter n reflect differences in reactivity of the initially formed dehydroalk aloid and can account for the toxicological differences between the pa rent PAs. (C) 1995 Academic Press, Inc.