Involvement of immune system mediators in exercise-mediated changes of hepatic cytochromes P450

Abstract

The physiological changes leading to exercise-mediated inhibition of hepatic cytochromes P450 have not been characterized. There is clinical evidence of increased release of cytokines (mediators of the immune system) after exercise. In addition, the modulation of P450 enzymes by nitric oxide (NOdot), another mediator of the immune system, has been demonstrated both in vivo and in vitro. Therefore, a series of experiments were designed to characterize the involvement of the immune system in exercise-mediated changes in P450. These experiments further evaluated the independent effects of exercise on the components of phase I-mediated drug metabolism. In vitro studies demonstrated that Spermine/NO (an NOdot donor) dramatically inhibited microsomal activity towards several P450 isozyme-specific substrates. In vivo studies with rats showed that treadmill running also resulted in an inhibition of P450 enzymatic activity towards substrates specific for P4502 family. These inhibitions were associated with a significant decrease in P450 reductase enzymatic activity and only small decreases in enzyme expression. Treatment of exercising rats with low levels of the antiinflamatory dexamethasone resulted in partial reversal of the inhibition. Dexamethasone alone produced no significant changes on the parameters measured. In addition, exercise was associated with an increase in the hepatic expression of the inducible form of nitric oxide synthase. These data support our hypothesis that the immune system is activated as a result of exercise. Further, the data support that exercise-induced alterations in immune mediators (i.e. NOdot) inhibit specific P450 metabolic pathways.