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

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 0.329 and 0.104 nmol/min/mg protein (DHP/N-oxide ratio of 3.16). The same microsomes produced DHP and SN N-oxide from [3H]SN at rates of 0.460 and 0.865 nmol/min/mg protein, yielding a DHP/N-oxide ratio of 0.53. Therefore, we concluded that the combinations of high pyrrole and low N-oxide formation, together with little hydrolysis, are the major factors responsible for the ready intoxication of guinea pigs by the PA JB.