Stimulation of hepatic drug-metabolizing enzymes by chlorophenothane (DDT); The relationship to liver enlargement and hepatotoxicity in the rat

Abstract

To study the relationship between induction of drug-metabolizing enzymes, liver enlargement and hepatotoxicity, we have administered DDT [1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane] to weanling male rats for 14 days. While administration of DDT at dietary concentrations of 0.5 or 2 ppm had no effect on the rate of p-nitroanisole ( p-NA) O-demethylation, concentrations of 4–750 ppm produced an increase in the rate of metabolism proportional to the log dose. Extrapolation of this portion of the dose-response curve to the abscissa provided a calculated no-effect level of 3.27 ± 1.02 ppm. At dietary concentrations greater than 750 ppm there was no further increase in p-NA metabolism. Liver weight increased in proportion to the dose when rats were maintained on diets containing 128–512 ppm DDT. Levels less than 128 ppm had no effect, and concentrations greater than 512 ppm produced a submaximal increase in liver weight. Although the total homogenate protein concentration (mg/g liver) was not affected by DDT administration, the microsomal protein concentration was increased by dietary concentrations above 16 ppm. Only in animals fed dietary levels above 750 ppm, in which there was no further increase in p-NA metabolism, were signs of neurotoxicity apparent. These results suggest that stimulation of drug-metabolizing enzymes, and the accompanying increase in liver weight and microsomal protein, are manifestations of a physiological adaptation.