Modulation of Drug Metabolism by Food Restiction

The effects of the level and duration of feed restriction on the in vitro activities of hepatic drug metabolizing enzyme system were examined in male weanling Sprague Dawley rats fed ad libitum or feed restricted at 15%, 30% and 45% for a period of one to five weeks (Experiment I). Increasing levels and duration of feed restriction resulted in significant progressive increases in hepatic microsomal protein, cytochrome P-450 content and the in vitro activities of microsomal aniline hydroxylase. p-chloro-methly-aniline(PCMA)N- demethylase and p-nitrophenol UDP-glucuronyl transferase activities were unaltered by the feed restriction while cytochrome c reductase activity was significantly decreased. In addition, the in vitro activities of the hepatic NADPH-generating enzymes were also significantly increased with the increasing levels and duration of feed restriction. It is concluded that the drug metabolizing enzymes did not necessarily change in concert with the cytochrome P-450 content and that prolonged feed restriction in healthy animals resulted in enhanced drug metabolizing capacity. This enhancement in drug metabolizing capacity was progressive with the increasing levels and duration of feed restriction. The greatest enhancement was observed when the animals were restricted at 45% for 4 or 5 weeks.

In two subsequent experiments, the in vivo metabolism of antipyrine and carbon tetrachloride toxicity were examined in rats feed restricted at 45% for four weeks. The feed restriction resulted in a significant decrease in the blood half-life of antipyrine and increased morbidity due to carbon tetrachloride. Thus feed restriction resulted in increased in vivo metabolism of xenobiotics and 45% feed restriction for four weeks was sufficient to cause a significant increase. These results supported the changes observed in the in vitro activities of the drug metabolizing system.