Jeong T C, Kim H J, Cha S W, Park J I, Shin H C, Kim D H, Han S S, Roh J K
Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon.
Immunopharmacol Immunotoxicol. 1996 Feb;18(1):91-103. doi: 10.3109/08923979609007112.
To investigate a possible role by cytochrome P450 (P450) in ethyl carbamate-induced immunosuppression, an attempt to assess the ability of ethyl carbamate, its metabolites produced by P450 (i.e., ethyl N-hydroxycarbamate and vinyl carbamate), and methyl carbamate to suppress the polyclonal antibody response induced by bacterial lipopolysaccharide was made in splenocyte cultures isolated from female Balb/C mice. The results showed that vinyl carbamate and ethyl N-hydroxycarbamate were more immunosuppressive compared to ethyl carbamate. A structurally related analogue, methyl carbamate, did not suppress the antibody response. These results indicate that metabolism of ethyl carbamate by P450 may produce more immunosuppressive metabolites as in ethyl carbamate-induced carcinogenicity. A pre-incubation study with phenobarbital-induced liver microsomes in the presence of NADPH-generating system showed that the antibody response was suppressed by ethyl carbamate when splenocytes were pre-incubated with ethyl carbamate and microsomes simultaneously. Moreover, the suppression was completely recovered by the addition of a P450 inhibitor, aminoacetonitrile, in the pre-incubation. Taken together, the present results indicate that metabolism of ethyl carbamate by P450 enzyme(s) may be an important pathway to cause immunosuppression.
为研究细胞色素P450（P450）在氨基甲酸乙酯诱导的免疫抑制中可能发挥的作用，我们尝试评估氨基甲酸乙酯、其由P450产生的代谢产物（即N-羟基氨基甲酸乙酯和氨基甲酸乙烯酯）以及氨基甲酸甲酯对从雌性Balb/C小鼠分离的脾细胞培养物中细菌脂多糖诱导的多克隆抗体反应的抑制能力。结果显示，与氨基甲酸乙酯相比，氨基甲酸乙烯酯和N-羟基氨基甲酸乙酯具有更强的免疫抑制作用。一种结构相关类似物氨基甲酸甲酯并未抑制抗体反应。这些结果表明，如在氨基甲酸乙酯诱导的致癌作用中一样，P450对氨基甲酸乙酯的代谢可能产生更强的免疫抑制性代谢产物。在存在NADPH生成系统的情况下，用苯巴比妥诱导的肝微粒体进行的预孵育研究表明，当脾细胞与氨基甲酸乙酯和微粒体同时预孵育时，氨基甲酸乙酯会抑制抗体反应。此外，在预孵育中加入P450抑制剂氨基乙腈可完全恢复这种抑制作用。综上所述，目前的结果表明，P450酶对氨基甲酸乙酯的代谢可能是导致免疫抑制的重要途径。
