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 metabolized by cytochrome P450 (P450) and esterase. It has recently been demonstrated that P450 may activate ethyl carbamate to immunotoxic metabolites. To investigate the role of esterase in ethyl carbamate-induced immunosuppression, mice were pretreated intraperitoneally with an esterase inhibitor, diazinon, at 20 mg/kg 30 min prior to the administration of ethyl carbamate intraperitoneally at 100 and 400 mg/kg for 7 consecutive days. Pretreatment with diazinon completely blocked the serum esterase activity. Histopathologically splenic and thymic atrophy was observed when mice were treated with ethyl carbamate, which was potentiated by the pretreatment with diazinon. In spleen, lymphocytes in the periarteriolar lymphoid sheath and the marginal zone appeared to be depleted in the white pulps. In thymus, ethyl carbamate caused 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 suggest 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 response induced by lipopolysaccharide and concanavalin A in splenocyte cultures. These results indicate that the metabolism of ethyl carbamate by P450 may be an activation pathway in immunosuppression by ethyl carbamate.
Cha
S W
SW
Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, South Korea.
Gu
H K
HK
Lee
K P
KP
Lee
M H
MH
Han
S S
SS
Jeong
T C
TC
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002219:Carbamates / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002452:Cell Count / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000097:blood*; D003208:Concanavalin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003976:Diazinon / Q000494:pharmacology; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D012756:Sheep; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014520:Urethane / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*
D002219:Carbamates; D002273:Carcinogens; D002800:Cholinesterase Inhibitors; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D003208:Concanavalin A; D014520:Urethane; C011286:N-hydroxyurethane; D003577:Cytochrome P-450 Enzyme System; C036868:methyl carbamate; D002802:Cholinesterases; D003976:Diazinon