Study on hepatotocicity of p-dichlorobenzene

rho-二氯苯（rho-DCB）被广泛用作飞蛾驱避剂和太空除臭剂。在用DL-丁硫氨磺酰亚胺（BSO ; 2 mmol/kg或更高剂量，i，p.）预处理的小鼠中，谷胱甘肽（GSH）合成抑制剂rho-DCB（100- 400 mg/kg，p.o.）通过血清丙氨酸氨基转移酶（ALT）活性和肝钙浓度增加以及肝脏组织学检查判断，导致剂量依赖性肝毒性。rho-DCB单独给药（高达1200 mg/kg）未导致肝毒性。GSH单乙酯是一种提高器官GSH水平的有效方法，可预防rho-DCB与BSO联合引起的肝毒性。用肝细胞色素rho-450依赖性单加氧酶抑制剂、二硫化碳、甲吡酮和胡椒基丁醚治疗也可预防肝毒性。这些结果表明，rho-DCB是由细胞色素rho-450依赖性代谢反应激活的，肝毒性是由BSO治疗导致肝GSH耗尽的小鼠中所产生的metamolite解毒率不足引起的。肝损伤之前，肝脏GSH的广泛消耗，但不伴随着肝脏脂质过氧化物和蛋白硫醇含量的显着变化。

rho-Dichlorobenzene (rho-DCB) is widely used as a moth repellent, and a space deodorant. In mice pretreated with DL-buthionine sulfoximine (BSO ; 2mmol/kg or higher doses, i, p.), an inhibitor of glutathione (GSH) synthesis, administration of rho-DCB (100-400mg/kg, p.o.) resulted in dose-dependent hepatotoxicity as judged by increased serum alanine aminotransferase (ALT) activities and liver calcium concentrations and by histologic examination of the liver. rho-DCB alone (up to 1200mg/kg) resulted in no hepatotoxicity. Administration of GSH monoethyl ester, which is known as a useful means for increasing organ GSH levels, protected against the hepatotoxicity caused by rho-DCB in combination with BSO.Treatment with inhibitors of hepatic cytochrome rho-450-dependent monooxygenases, carbon disulfide, metyrapone, and piperonyl butoxide, also prevented the hepatotoxicity. These results suggest that rho-DCB is activated by a cytochrome rho-450-dependent metabolic reaction and that the hepatotoxicity is caused by inadequate rates of detoxification of the resulting metamolite in mice depleted of hepatic GSH by BSO treatment. The liver injury was preceded by an extensive depletion of hepatic GSH but not accompanied by significant changes in hepatic contents of lipid peroxides and protein thiols.