Date of Award

1971

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Interdepartmental Program

First Advisor

John J. DeFeo

Abstract

Liver enlargement in rats resulting from oral administration of pyrethrum has been observed in various laboratories. This study was undertaken to investigate the nature of this enlargement as well as resulting changes in hepatic drug metabolism. Oral administration of pyrethrum at 200 mg/kg for 13 or 23 days resulted in decreases in hepatic DNA concentrations. While total lipid concentrations were increased significantly, the increases did not account for the enlargement. Protein concentrations of whole liver homogenates, 9,000 x g supernatants and the 105,000 x g pellet were not different from controls. No significant changes occurred in hepatic water concentrations. Accompanying histological observations of the enlarged livers indicated cellular hypertrophy.

Significant decreases in hexobarbital induced hypnosis without concomitant changes ir1 barbital induced hypnosis suggested a pyrethrum caused alteration in hepatic drug metabolism. The activities of hepatic microsomal enzymes responsible for EPN detoxification, p-nitroanisole demethylation and hexobarbital oxidation were increased to 150, 173 and 241 percent of control, respectively. No significant increases were noted in the demethylation of aminopyrina or oxidation of L-tryptophan. Increases in liver weight, the detoxification of EPN and demethylation of p-nitroanisole were found to be dose related. Increased enzyme activities were observed at the lowest dose used of 85 mg/kg/d3y for 15 days. At a dose of 500 mg/kg/day, liver weights and enzyme activities were increased continually during a 17 day period of treatment but returned to control level within 7 days after cessation of treatment. NADPH-cytochrome c reductase and P-450 concentrations were also increased. These data show that pyrethrum causes significant liver enlargement with accompanying increases in microsomal drug metabolizing activity. They suggest a re-evaluation of the use of pyrethrum as a non-inducing insecticide.

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