CYP2E1在小鼠1,2-二氯乙烷中毒性肝损伤中的作用

Roles of CYP2E1 in liver damage induced by 1,2-dichloroethane

目的探讨亚急性1,2-二氯乙烷(1,2-DCE)染毒对小鼠肝微粒体中CYP2E1表达的影响及其在1,2-DCE中毒性肝损伤中的作用。方法 (1)将32只昆明种雌性小鼠随机分为对照组及1,2-DCE低、中和高剂量染毒组,染毒剂量分别为0.225、0.45和0.9 g/m3。采用静式吸入方式对小鼠染毒10 d,末次染毒的次日,处死小鼠,迅速取血和肝组织。对肝组织进行病理学观察,并检测血中丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)活性及肝微粒体中CYP2E1蛋白表达和活性。(2)将60只昆明种雌性小鼠随机分为空白对照组、玉米油对照组、二烯丙基硫化物(DAS)对照组、单纯染毒组及低和高剂量DAS干预组(150和300 mg/kg)。将DAS溶于玉米油中,于1,2-DCE染毒前4 h通过灌胃给予DAS。1,2-DCE染毒时间及检测指标同上。结果 (1)中、高剂量染毒组小鼠肝组织出现不同程度病理性损伤;高剂量染毒组小鼠血清中ALT活性显著高于对照组(P<0.05);中、高剂量染毒组小鼠肝微粒体中CYP2E1蛋白表达和活性与对照组相比均显著升高(P<0.05)。(2)高剂量DAS干预组小鼠肝细胞病理损伤明显改善,其小鼠血清中ALT活性也显著低于单纯染毒组(P<0.05);低、高剂量DAS干预组小鼠肝微粒体中CYP2E1蛋白表达和酶活性均显著低于单纯染毒组(P<0.05)。结论 1,2-DCE染毒可明显诱导肝微粒体中CYP2E1蛋白的表达,并导致肝组织损伤,DAS通过抑制CYP2E1蛋白的表达可以减轻1,2-DCE引起的肝损伤。

Objective To explore the expression of CYP2E1 in the liver of mice and its effects on liver injury induced by 1,2-dichloroethane（ 1,2-DCE）. Methods（ 1）Thirty-two female mice were randomly divided into four groups,which were control group,low dose group,medium dose group and high dose group. Mice were exposed to 1,2-DCE through respiratory for 4 h per day for 10 days. At the end of exposure,the mice were sacrificed, their blood and liver were collected rapidly. Pathological analysis was examined. Activity of ALT and AST in serum and activity of CYP2E1 in liver weremeasured. Expression of CYP2E1 in liver was detected by western blot.（ 2） Sixty female mice were randomly divided into six groups,ie,simple control group,corn oil control group,inhibitor control group,simple poisonous group,low and high dose diallyl sulfide（ DAS） intervention groups. Mice were treated orally with DAS in corn oil 4 hours before1,2-DCE exposure. The examination indicators were as aforementioned. Results（ 1）Compared to control group,activity of ALT in serum of mice in the high dose group and expression of CYP2E1 in the liver of mice in medium and high dose group increased significantly. In addition,the histological observation suggested obvious liver damage in medium and high dose group.（ 2） CYP2E1 protein expression and activity in liver and ALT in serum decreased significantly in DAS-intervention groups compared to simple poisonous group. Along with the changes of CYP2E1 and ALT,pathological changes of liver damage was better. Conclusion Our results suggested that expression of CYP2E1 and oxidative damage in the liver could be induced by 1,2-DCE exposure,and CYP2E1 inhibitors can reduce the hepatic tissue damage caused by DCE.