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

John B. Watkins, Ruth A. Sanders, Lyle V. Beck

Research output: Contribution to journalArticle

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Abstract

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 μl 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 μl CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 μl/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.

Original languageEnglish
Pages (from-to)329-338
Number of pages10
JournalToxicology and Applied Pharmacology
Volume93
Issue number2
DOIs
StatePublished - 1988

Fingerprint

Experimental Diabetes Mellitus
Carbon Tetrachloride
Streptozocin
Medical problems
Biotransformation
Rats
Dinitrochlorobenzene
Liver
Sulfobromophthalein
Estrone
Glutathione Transferase
Enzyme activity
Enzymes
N Demethylating Oxidoreductases
Benzphetamine
Testosterone
Ethacrynic Acid
Glucuronosyltransferase
Ketosis
Diethylstilbestrol

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. / Watkins, John B.; Sanders, Ruth A.; Beck, Lyle V.

In: Toxicology and Applied Pharmacology, Vol. 93, No. 2, 1988, p. 329-338.

Research output: Contribution to journalArticle

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