It is widely known that the clearance of drugs is often compromised during episodes of
infectious disease via a down-regulation of
cytochrome P450 (P450) at a pre-translational step in
enzyme synthesis.
Etiocholanolone (ETC), a potent inflammatory agent, induces
fever in humans and causes a decrease in the clearance of certain drugs that are metabolized by P450. On this basis it is widely believed that the
fever per se rather than the immune modulation that occurs during
infections may have a major role in depression of microsomal
P450 enzymes during
viral infections in humans. In the present study, we demonstrated that although ETC did not induce
hyperthermia in mice, it still evoked a depression of the levels of P450 in hepatic microsomes.
Ethoxyresorufin O-deethylase (
EROD) was also inhibited significantly when hepatic microsomes were incubated with various concentrations of ETC in vitro. P450 levels and
EROD activities remained unchanged following
hyperthermia that was induced by a non-inflammatory procedure using
2,4-dinitrophenol. Provided the response in rodents is similar to humans, these results indicate that the depression of
drug biotransformation by ETC in humans is more likely to be caused by the direct effects of this agent or other mechanisms rather than by the
fever it produces. This may suggest that the loss of
drug metabolism in humans during
infections is due to the activation of host defence responses rather than to the febrile nature of the illness.