Role of interleukin-1beta in the modulations of cytochrome P450 and heme metabolism in rat liver.
The effect of recombinant human interleukin-1beta (IL-1beta) on the modulation of hepatic cytochrome P450 (P450) was investigated by in vivo subcutaneous dosing studies in male Sprague-Dawley rats. To assess the effect of IL-1beta on heme metabolism, we determined the delta-aminolevulinic acid synthetase (delta-ALAS) and heme oxygenase activities in the liver. IL-1beta suppressed the microsomal total P450 and heme contents and delta-ALAS activity in the liver. In contrast, microsomal heme oxygenase activity was significantly increased by the IL-1beta treatments. Western blot analysis and marker enzyme activities for individual P450 isoforms demonstrated that IL-1beta suppressed CYP2C6, 2C13, 2E1, and 3A2, whereas CYP2A, 2B1/2, 2C11, and 4A1 were not influenced by the treatments. IL-1beta inhibited both allylisopropylamide- and phenobarbital-inducible delta-ALAS activities in the liver. These results indicate that IL-1beta has differential effects on the constitutive P450, and also on delta-ALAS and heme oxygenase activities in rat liver. Thus, the modulation of hepatic P450 by IL-1beta is complex, and IL-1beta may be involved in the regulation of both apoprotein synthesis for each P450 isoform and the heme pools in the liver.
Kudo
S
S
Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan. s_kudo@research.otsuka.co.jp
Kawano
K
K
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007375:Interleukin-1; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital