Exercise-induced inhibition of hepatic drug metabolism and a mechanism for decreased activity of P450IIE1 in Fischer-344 rats

Abstract

Clinical studies have appeared in the literature suggesting that exercise affects the pharmacokinetics of numerous drugs. However, there have been a minimal number of carefully controlled animal studies which have used only a few substrates and have lacked specific hepatic biochemical (enzymatic) determinations; thus, definite conclusions could not be drawn. In light of these facts, a series of experiments were designed to characterize, quantify and test a mechanism for the effects of exercise on components of the hepatic drug metabolizing systems in young, middle-aged (M-A) and aged rats exercised by either treadmill running or swimming. Running resulted in a dramatic substrate specific inhibition on P450 content and activity in all age groups. Furthermore, running resulted in complete protection from CCl{dollar}\sb4{dollar} toxicity (CCl{dollar}\sb4{dollar} is activated by P450) in young and M-A rat hepatocytes incubated with this solvent. Results of in vivo HB sleep time studies in young rats (sleep time is dependent on P450-mediated metabolism of HB) also correlated with the running-induced inhibition of microsomal P450 in vitro. With regard to swimming exercise, results indicate that exposure to water confounds the results, and when appropriate controls were considered, no effect on any microsomal parameter was found. Glucuronidation of pNP was increased with running whereas sulfation was unaffected in young and M-A rat hepatocytes. After 8 wk of running, metabolism of aniline and HB is significantly inhibited; however, after 3 wk, in vivo studies show HB metabolism is significantly declined, while in vitro studies reveal no effect on aniline metabolism. Since each substrate is metabolized by separate isozymes, different mechanisms may be involved. Investigations into a possible mechanism for running-induced inhibition of aniline metabolism and CCl{dollar}\sb4{dollar} toxicity (both are selectively metabolized by P450IIE1) has revealed a decrease in the amount of apoprotein and mRNA which are ultimately responsible for the formation of the active isozyme. These studies indicate that exercise has isozymal-selective effects on drug metabolism and may also be useful as a probe for studying P450 regulation and function. Furthermore, since P450IIE1 is responsible for the activation of nitrosamines which are a major group of carcinogens, exercise-induced inhibition of P450IIE1 may be related to reports of decreased cancer with regular exercise. However, this remains to be determined.