ROLE OF METABOLISM IN MONOCROTALINE-INDUCED IMMUNOTOXICITY IN C57BL 6MICE/

Monocrotaline (MCT) is a pyrrolizidine alkaloid which has been shown t o induce immunotoxicity in mice. We hypothesized that metabolic activa tion of MCT by mixed-function oxygenases (MFO) to dehydromonocrotaline (MCTP) is a prerequisite for its immunotoxicity, as has been shown fo r 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 cel l mitogens. In addition, the effects of in vivo modulation of MFO acti vities 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 increas ed 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 m ore potent than MCT, a role for the MCTP metabolite in MCT immunotoxic ity in vivo could not be demonstrated.