Metabolism of [14C]monocrotaline by isolated perfused rat liver.
The metabolism of the pyrrolizidine alkaloid [14C]monocrotaline [( 14C]MCT) was examined using the in situ isolated perfused rat liver. Hepatic tissue was perfused in a recirculatory fashion for 90 min and the distribution of metabolites between the bile and perfusate was analyzed. Monocrotalic acid (MCA) was found to be the major acidic metabolite of [14C]MCT, with trace amounts of 1-formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), and 1-hydroxymethyl-7-oxo-6,7-dihydro-5H-pyrrolizine (tentative assignment) being identified in the perfusates using GC/MS. MCT N-oxide was also identified but represented less than 4% of the perfusate 14C. The simple necine base retronecine was not present at detectable levels in the perfusion medium. A large portion of the 14C recovered from both the bile and perfusate was not extractable, under acidic or basic conditions, into organic solvents. Using fast atom bombardment MS/MS, a portion of this material was identified as a glutathione conjugate of DHP. In addition, this nonextractable material retained a portion of the radioactivity that was equivalent to the acidic fraction. Given these findings and the absence of retronecine, the major pathway for the metabolism of MCT could potentially involve the production of MCT pyrrole, which subsequently reacts with cellular nucleophiles producing MCA in addition to highly water-soluble conjugated pyrroles and possibly macromolecular adducts.
Lamé
M W
MW
Department of Veterinary Pharmacology and Toxicology, University of California, Davis 95616.
Jones
A D
AD
Morin
D
D
Segall
H J
HJ
D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D016686:Monocrotaline; D011485:Protein Binding; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D005978:Glutathione