Immunotoxicity of ethyl carbamate in female BALB/c mice: role of esterase and cytochrome P450

Ethyl carbamate, a potent carcinogen, has been characterized to be metaboli zed by cytochrome P450 (P450) and esterase. It has recently been demonstrat ed that P450 may activate ethyl carbamate to immunotoxic metabolites. To in vestigate the role of esterase in ethyl carbamate-induced immunosuppression , mice were pretreated intraperitoneally with an esterase inhibitor, diazin on, at 20 mg/kg 30 min prior to the administration of ethyl carbamate intra peritoneally at 100 and 400 mg/kg for 7 consecutive days. Pretreatment with diazinon completely blocked the serum esterase activity. Histopathological ly splenic and thymic atrophy was observed when mice were treated with ethy l carbamate, which was potentiated by the pretreatment with diazinon. In sp leen, lymphocytes in the periarteriolar lymphoid sheath and the marginal zo ne appeared to be depleted in the white pulps. In thymus, ethyl carbamate c aused a marked depletion of cells in cortex. The antibody response to sheep red blood cells (SRBCs) was more suppressed by ethyl carbamate in diazinon -pretreated groups than in corn oil-pretreated groups. These results sugges t that the metabolism of ethyl carbamate by esterase may be an inactivation pathway in ethyl carbamate-induced immunosuppression. In addition, ethyl N -hydroxycarbamate, a P450 metabolite, suppressed the lymphoproliferative re sponse induced by lipopolysaccharide and concanavalin A in splenocyte cultu res. These results indicate that the metabolism of ethyl carbamate by P450 may be an activation pathway in immunosuppression by ethyl carbamate. (C) 2 000 Published by Elsevier Science Ireland Ltd. All rights reserved.