The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats.

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.