PMID: 8591728Nov 1, 1995Paper

Major factors for the susceptibility of guinea pig to the pyrrolizidine alkaloid jacobine

Drug Metabolism and Disposition : the Biological Fate of Chemicals
W G Chung, D R Buhler

Abstract

Guinea pigs are generally resistant to the toxicity of pyrrolizidine alkaloids (PAs). However, the PA jacobine (JB) is unusually toxic to this species. We now have investigated whether different pathways for JB metabolism in the guinea pig could contribute to the susceptibility of this species to this PA. To investigate the potential for esterolytic cleavage of PAs, we have initially purified two forms of hepatic carboxylesterase (GPL1 and GPH1) from guinea pigs. The major form (GPL1) was purified to a specific activity of 486 mumol/min/mg protein in the hydrolysis of p-nitrophenyl acetate (NPA), whereas the minor form (GPH1) yielded p-nitrophenol with a specific activity of 86 mumol/min/mg protein from NPA. The metabolism of the highly toxic PA jB and the less toxic PA seneclonine (SN) was studied using 3H-labeled PAs with guinea pig liver microsomes and purified guinea pig carboxylesterases. Purified carboxylesterase (GPH1) hydrolyzed [3H]JB and [3H]SN at rates of 4.5 and 11.5 nmol/min/mg protein, respectively. Carboxylesterase GPL1, however, had no activity toward these PAs. Liver microsomes converted [3H]JB to the pyrrolic metabolite (+/-) 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) and JB N-oxide at rates of...Continue Reading

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