The comparative metabolism of the four pyrrolizidine alkaloids, seneciphylline, retrorsine, monocrotaline, and trichodesmine in the isolated, perfused rat liver.
Despite their similarity in structure, pyrrolizidine alkaloids (PAs) vary in their LD50s and in the organs in which toxicity is expressed. We have examined whether there are differences in the metabolism of certain PAs that are associated with these quantitative and qualitative differences 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 were released into perfusate and bile or bound in the liver. The proportion of the PA removed by the liver varied from 93% for retrorsine to 55% for trichodesmine. However, trichodesmine-perfused livers released the greatest amount of the dehydroalkaloid into the perfusate. These reactive pyrrolic metabolites appear to be largely responsible for the toxicity of PAs. Over the course of a 1-hr perfusion, dehydroalkaloid release varied fourfold among the PAs examined. Seneciphylline and retrorsine significantly increased bile flow. Highest concentrations of PAs in bile were achieved at 30-40 min perfusion. Conversion of dehydroalkaloid 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 dehydroalkaloids, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine, was also determined. Bound pyrroles in liver are probably an indication of heptatoxicity. At the end of perfusion these varied from 55 nmol/g for monocrotaline 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 only monoalkylation has been found. These differences in metabolic pattern reflect differences in reactivity of the initially formed dehydroalkaloid and can account for the toxicological differences between the parent PAs.
Yan
C C
CC
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724, USA.
Cooper
R A
RA
Huxtable
R J
RJ
D000470:Alkaloids / Q000378:metabolism* / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000633:toxicity; D001646:Bile / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016686:Monocrotaline / Q000378:metabolism* / Q000633:toxicity / Q000031:analogs & derivatives; D010477:Perfusion; D011758:Pyrroles / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
C091658:7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; C013678:seneciphylline; C004250:trichodesmine; D016686:Monocrotaline; D005978:Glutathione; C003300:retrorsine