Study on hepatotocicity of p-dichlorobenzene

rho-二氯苯（rho-DCB）被广泛用作防蛾剂和空间除臭剂。通过血清谷丙转氨酶（ALT）活性和肝脏钙浓度的升高以及肝脏组织学检查，对小鼠进行dl -丁硫氨酸亚砜（BSO， 2mmol/kg或更高剂量，1,p.）（一种谷胱甘肽（GSH）合成抑制剂）预处理，rho-DCB （100-400mg/kg, p.o.）可导致剂量依赖性肝毒性。单独使用rho-DCB（高达1200mg/kg）不会导致肝毒性。GSH单乙基酯的管理，被认为是增加器官GSH水平的有效手段，防止rho-DCB与BSO联合引起的肝毒性。用肝细胞色素rho-450依赖的单加氧酶抑制剂、二硫化碳、美替拉酮和胡椒酰丁醇也可预防肝毒性。这些结果表明，rho-DCB是由细胞色素rho-450依赖的代谢反应激活的，肝毒性是由BSO处理后肝脏GSH衰竭的小鼠产生的代谢物解毒率不足引起的。肝损伤发生前肝谷胱甘肽大量耗竭，但不伴有肝脏脂质过氧化物和蛋白质硫醇含量的显著变化。

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.