Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes

Recent metabolic studies have demonstrated the importance of reactive inter mediates like quinones or semiquinone radicals in the covalent binding of h alobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobe nzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-elect ron reduction of the quinone intermediates by DT-diaphorase is considered t o be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisol e (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dico umarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BE (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p .). Dietary BHA markedly suppressed the hepatotoxicity caused by both BE an d 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BE at differ ent times after the end of dietary BHA exposure, the degree of the protecti on against the hepatotoxicity appears to correlate to the extent of the ind uction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment fail ed to protect against carbon tetrachloride-induced hepatotoxicity. These re sults seem to provide evidence for the involvement of the quinone metabolit es in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity. (C) 1999 Elsevier Science Ireland Lt d. All rights reserved.