The role of metabolism in chloroform hepatotoxicity

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Abstract

Since there is indirect evidence that a metabolite may be responsible for the hepatotoxicity of CCl4, the possibility that chloroform may also act through a similar mechanism was investigated. Pretreatment with stimulators of drug metabolizing enzymes like phenobarbital, 3-methylcholanthrene or 3,4-benzopyrene increased the toxicity of chlorform in rats, as reflected by increased serum glutamic-pyruvic transaminase and a decrease in liver glucose-6-phosphatase activity. This enhancement of the toxicity of CHCl3 was associated with an increase in 14CHCl3 metabolism, as measured by pulmonary excretion of 14CO2. An inhibitor of drug metabolizing enzymes, SKF 525-A, was found to decrease pulmonary excretion of 14CO2. If these observations may be taken as indirect evidence that the hepatotoxic effect of CHCl3 is due to a metabolite, other data do not seem to support such an hypothesis. No metabolite of CHCl3 could be detected by gas-liquid chromatography; there was no quantitative correlation between the increase in toxicity and the increase in CHCl3 metabolism. Finally, SKF 525-A did not decrease CHCl3 hepatotoxicity. It is concluded that metabolism of CHCl3 may be involved in the hepatotoxic effect of CHCl3, but other factors may also play a role in determining this response.

References (33)

  • R.J. Stenger et al.

    Effects of phenobarbital pretreatment on the hepatotoxicity of carbon tetrachloride

    Exp. Mol. Pathol.

    (1970)
  • K.A. Suarez et al.

    Differential acute effects of phenobarbital and 3-methylcholanthrene pretreatment on CCl4-induced hepatotoxicity in rats

    Toxicol. Appl. Pharmacol.

    (1972)
  • G. Ugazio et al.

    Mechanism of protection against carbon tetrachloride by prior carbon tetrachloride administration

    Exp. Mol. Pathol.

    (1972)
  • R.A. Van Dyke et al.

    Metabolism of volatile anesthetics. I. Conversion in vivo of several anesthetics to 14CO2 and chloride

    Biochem. Pharmacol.

    (1964)
  • T. Ariyoshi et al.

    Die Wirkung von Phenobarbital und Diphenylhydantoin auf verschiedene

    Naunyn-Schmiedeberg's Arch. Pharmakol.

    (1968)
  • J. Brodeur et al.

    Effect of splenectomy on the activity of drugmetabolizing enzymes in the liver of rats

    Can. J. Physiol. Pharmacol.

    (1971)
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