Date of Award

1972

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacology and Toxicology

Department

Pharmaceutical Sciences

First Advisor

George C. Fuller

Abstract

Phenobarbital pretreatment significantly enhanced the rise in SGOT and SGPT immediately following a three-hour exposure of rats to carbon tetrachloride by inhalation. However, these parameters of hepatotoxicity were significantly lower in rats pretreated with 3-methylcholanthrene when compared to rats pretreated with vehicle and exposed to carbon tetrachloride vapor. Levels of hepatic microsomal NADPH cytochrome c reductase and CO-binding pigment were elevated by phenobarbital pretreatment, but 3-methylcholanthrene had no effect on hepatic microsomal NADPH cytochrome c reductase. Although carbon tetrachloride exposure reduced CO-binding pigment content by 61 per cent in phenobarbital pretreated and by 39 per cent in 3-methylcholanthrene pretreated rats, microsomal NADPH cytochrome c reductase was reduced by only 6 per cent and 20 per cent, respectively. In phenobarbital pretreated rats, exposure to carbon tetrachloride produced a greater decrease in aminopyrine demethylase activity than in saline treated carbon tetrachloride exposed controls. However, in 3-meteyleholanthrene pretreated rats, exposure to carbon tetrachloride produced a lesser decrease in p-nitroanisole demethylase activity than in corn oil treated controls. Twenty-one hours after exposure, the difference in SGOT and SGPT values of the phenobarbital and 3-methylcholanthrene pretreated rats was more divergent. Histological evidence at this time period revealed extensive damage in the phenobarbital pretreated. animals and a spring effect in the 3-methylcholanthrene pretreated animals.

While phenobarbital pretreatment enhanced the microsomal diene conjugation absorption indicative of lipid peroxidation following carbon tetrachloride exposure, 3-methylcholanthrene pretreatment had the opposite effect. Carbon monoxide, but not hypoxia, enhanced the increase in SGOT, SGPT, and microsomal diene conjugation absorption following exposure to carbon tetrachloride. These data suggest that the differential effects of 3-methylcholanthrene and phenobarbital pretreatment on NADPH cytochrome c reductase and CO-binding pigment may be responsible for the observed protective effect of 3-methylcholanthrene in carbon tetrachloride exposed rats.

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