Effect of interleukin 1 beta-induced fever on hepatic drug metabolism in rat.
1. A fever-induced model in rat was created by repeated injection of interleukin 1 beta (IL-1 beta) in the cerebroventricle and the influence of fever on hepatic drug metabolism was investigated. Fever apparently decreased the content of cytochrome P450 (CYP) and the activities of NADPH-ferrihaemoprotein reductase (fp2), aminopyrine N-demethylase, aniline hydroxylase, FAD-monooxygenase, p-nitrophenol UDP-glucuronosyl-transferase and glutathione S-transferase. Immunoblot analysis of the CYP isozymes indicated that CYP2C11 and CYP3A were extensively decreased in the IL-1 beta-induced fevered rat. 2. Repeated administration (5 days) of mefenamic acid in the fevered rat could not restore the activities of fp2, aminopyrine N-demethylase and aniline hydroxylase to control levels, although their hyperthermic state had been improved. The CYP content in the mefenamic acid-treated fevered rat was also lower than that in the control. 3. These findings suggest that fever impairs the hepatic drug-metabolizing capacity (both oxidation and some conjugations) and that the fever-induced impairments are partially retained, even if the hyperthermia has been offset by the administration of antipyretics.
Department of Biochemistry, Faculty of Pharmaceutical Science, Fukuoka University, Japan.
T
T
Kihara
A
A
Toda
I
I
Umesue
N
N
Ono
H
H
Shigematsu
S
S
Soeda
H
H
Shimeno
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced / Q000201:enzymology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000008:administration & dosage / Q000633:toxicity*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity
D007375:Interleukin-1; D007527:Isoenzymes; D011994:Recombinant Proteins; D008528:Mefenamic Acid; D003577:Cytochrome P-450 Enzyme System; D005979:Glutathione Peroxidase; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase