Preservation of glucuronidation in carbon tetrachloride-induced acute liver injury in the rat

Paul V. Desmond, Robert James, Steven Schenker, John F. Gerkens, Robert A. Branch

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28 Scopus citations

Abstract

The influence of carbon tetrachloride on several routes of drug metabolism has been investigated in the rat in vivo, in isolated perfused livers, and in hepatic microsomal preparations to evaluate the hypothesis that hepatic glucuronyl transferase activity is preserved when mixed-function oxidase activity is impaired by this hepatotoxin. Impaired oxidative metabolism after acute administration of carbon tetrachloride was confirmed in vivo by a 65 per cent reduction in the rate of elimination of 14CO2 in breath after [14C]aminopyrine administration and a 58 per cent reduction in the clearance of lorazepam in the whole animal. In the isolated perfused livers of control rats, glucuronide metabolism of lorazepam accounted for 26 per cent of its overall elimination; thus, by inference, oxidative metabolism accounted for the remainder. Carbon tetrachloride pretreatment resulted in a 63 per cent reduction in total lorazepam clearance. In microsomal preparations, cytochrome P-450 concentration, cytochrome P-450 reductase activity, and activities of o-demethylation of p-nitroanisole and hydroxylation of aniline were reduced by 63, 32, 85 and 95 per cent, respectively, after exposure to carbon tetrachloride. In contrast, in the carbon tetrachloride-damage isolated perfused liver the proportion of lorazepam conjugated to lorazepam glucuronide increased from 26 to 43 per cent of the dose administered. Furthermore, in vitro microsomal glucuronidation of o-aminophenol was not decreased by carbon tetrachloride pretreatment, while glucuronidation of p-nitrophenol actually increased significantly by 49 per cent. Solubilization of microsomes with Triton X-100 resulted in a 10.4-fold increase in glucuronyl transferase activity in control microsomes, but in only a 5.7-fold increase in microsomes from carbon tetrachloride-treated rats. This suggests that carbon tetrachloride enhanced basal glucuronidating activity but decreased the total amount of enzymes present. These overall results suggest that microsomal glucuronidation activity is spared in an experimental liver injury in which oxidative metabolism is impaired.

Original languageEnglish (US)
Pages (from-to)993-999
Number of pages7
JournalBiochemical Pharmacology
Volume30
Issue number9
DOIs
StatePublished - May 1 1981
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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