p-Dichlorobenzene-induced hepatotoxicity in mice depleted of glutathione by treatment with buthionine sulfoximine.
p-Dichlorobenzene (p-DCB) is widely used as a moth repellent and a space deodorant. In mice pretreated with DL-buthionine sulfoximine (BSO; 2 mmol/kg or higher doses, i.p.), an inhibitor of glutathione (GSH) synthesis, administration of p-DCB (100-400 mg/kg, p.o.) resulted in dose-dependent hepatotoxicity as judged by increased serum alanine aminotransferase (ALT) activities and liver calcium concentrations and by histological examination of the liver, p-DCB alone (up to 1200 mg/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 p-DCB in combination with BSO. Treatment with inhibitors of hepatic cytochrome P-450-dependent monooxygenases, carbon disulfide, metyrapone and piperonyl butoxide also prevented the hepatotoxicity. These results suggest that p-DCB is activated by a cytochrome P-450-dependent metabolic reaction and that the hepatotoxicity is caused by inadequate rates of detoxification of the resulting metabolite 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.
Mizutani
T
T
Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.
Nakahori
Y
Y
Yamamoto
K
K
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019328:Buthionine Sulfoximine; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002722:Chlorobenzenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000172:deficiency / Q000502:physiology*; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D000069463:Olive Oil; D010938:Plant Oils / Q000494:pharmacology
D002273:Carcinogens; D002722:Chlorobenzenes; D007306:Insecticides; D000069463:Olive Oil; D010938:Plant Oils; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C018511:4-dichlorobenzene; D000410:Alanine Transaminase; D005978:Glutathione; D002118:Calcium; D008797:Metyrapone