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 intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (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 BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.
Mizutani
T
T
Department of Food Sciences and Nutritional Health, Kyoto Prefectural University, Shimogamo, Japan. mizutani@kpu.ac.jp
Miyamoto
Y
Y
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001969:Bromobenzenes / Q000037:antagonists & inhibitors / Q000633:toxicity; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000517:prevention & control; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000517:prevention & control*; D002722:Chlorobenzenes / Q000037:antagonists & inhibitors / Q000633:toxicity; D001728:Dicumarol / Q000494:pharmacology*; D004032:Diet; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
D001555:Benzene Derivatives; D001969:Bromobenzenes; D002722:Chlorobenzenes; D004791:Enzyme Inhibitors; C009947:1,2,4-trichlorobenzene; D002083:Butylated Hydroxyanisole; D001728:Dicumarol; C032036:bromobenzene; D016660:NAD(P)H Dehydrogenase (Quinone); D000410:Alanine Transaminase