Role of metabolism in monocrotaline-induced immunotoxicity in C57BL/6 mice

Monocrotaline (MCT) is a pyrrolizidine alkaloid which has been shown to induce immunotoxicity in mice. We hypothesized that metabolic activation of MCT by mixed-function oxygenases (MFO) to dehydromonocrotaline (MCTP) is a prerequisite for its immunotoxicity, as has been shown for other toxic effects of MCT. To test this hypothesis, we compared the in vitro immunotoxic potency of MCT and MCTP to suppress the in vitro antibody response to SRBC and the blastogenic response to B and T cell mitogens. In addition, the effects of in vivo modulation of MFO activities on the immunotoxicity of MCT was examined using phenobarbital (PB) to increase and chloramphenicol (CP) to decrease MCTP production. Results showed that in vitro exposure of splenic lymphocytes to MCT or MCTP produced significant suppression of the antibody and blastogenic responses. MCTP was 200-400-fold more potent than MCT. No metabolism of MCT by splenic cells was detectable, suggesting that unmetabolized MCT is capable of inducing immunotoxicity. In vivo studies showed that, while treatment of mice with PB or CP produced significantly increased and decreased MCTP production by liver microsomes, neither PB or CP treatment significantly altered the immunotoxic potency of MCT. Thus, while the MCTP metabolite is directly immunotoxic in vitro and much more potent than MCT, a role for the MCTP metabolite in MCT immunotoxicity in vivo could not be demonstrated.