EFFECTS OF ETHYL CARBAMATE AND ITS METABOLITES ON THE ANTIBODY-RESPONSE IN SPLENOCYTE CULTURES FROM FEMALE BALB C MICE/

To investigate a possible role by cytochrome P450 (P450) in ethyl carb amate-induced immunosuppression, an attempt to assess the ability of e thyl carbamate, its metabolites produced by P450 (i.e., ethyl N-hydrox ycarbamate and vinyl carbamate), and methyl carbamate to suppress the polyclonal antibody response induced by bacterial lipopolysaccharide w as made in splenocyte cultures isolated from female Balb/C mice. The r esults showed that vinyl carbamate and ethyl N-hydroxycarbamate were m ore immunosuppressive compared to ethyl carbamate. A structurally rela ted analogue, methyl carbamate, did not suppress the antibody response . These results indicate that metabolism of ethyl carbamate by P450 ma y produce more immunosuppressive metabolites as in ethyl carbamate-ind uced carcinogenicity. A pre-incubation study with phenobarbital-induce d liver microsomes in the presence of NADPH-generating system showed t hat the antibody response was suppressed by ethyl carbamate when splen ocytes were pre-incubated with ethyl carbamate and microsomes simultan eously. Moreover, the suppression was completely recovered by the addi tion of a P450 inhibitor, aminoacetonitrile, in the pre-incubation. Ta ken together, the present results indicate that metabolism of ethyl ca rbamate by P450 enzyme(s) may be an important pathway to cause immunos uppression.