Date of Award

1969

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

George C. Fuller

Abstract

Male rats were exposed to methylchloroform (1,1,1-tricholoethane) vapors (concentration about 2500 PPM) for 24 hours and the effects of this treatment on drug responses and hepatic drug metabolism studied 24 hours later to determining the effect of methylchloroform on inducible hepatic drug-metabolizing enzymes. Exposure to methylchloroform vapor significantly decreased the sleeping time of the rat in response to hexobarbital (120 mg/kg, i.p.) and zoxazolamine (80mg/kg, i.p.). Rat blood and liver methylchloroform content measured immediately following exposure suggested that the effects of methylchloroform were caused by a systemic action. Experiments with 9000 x G supernatants indicated that the metabolism of hexobarbital was significantly increased following exposure to methylchloroform. Significantly increased N-demethylation of aminopyrine, accompanied by increased amounts of microsomal CO-binding pigment (cytochrome P-450) and microsomal NADPII-cytochrome c reductate were observed in vitro experiments using hepatic microsomal fractions from rats exposed to methylchloroform. The spectral properties of the CO-binding pigment in animals exposed to methylchloroform did not differ from controls Pretreatment with actinomycin D or cycloheximide prevented the decrease in the hexobarbital sleeping time in rats exposed to methylchloroform. Further studies demonstrated that pretreatment with cycloheximide prevented the increase in metabolism of aminopyrine by rats exposed to methylchloroform. These observations suggest that the increased drug-metabolizing activity in the exposed rats is due to an accelerated synthesis of the hepatic drug-metabolizing system. The inducing effects of methylchloroform appear to be related to those produced by phenobarbital.

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