Modulatory effect of hyperthermia on hepatic microsomal cytochrome P450 in mice.
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.
Anari
M R
MR
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Renton
K W
KW
D019297:2,4-Dinitrophenol; D000818:Animals; D001711:Biotransformation; D001831:Body Temperature / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004140:Dinitrophenols / Q000494:pharmacology; D015536:Down-Regulation; D005043:Etiocholanolone / Q000494:pharmacology; D006979:Hyperthermia, Induced; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004140:Dinitrophenols; D003577:Cytochrome P-450 Enzyme System; D005043:Etiocholanolone; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019297:2,4-Dinitrophenol