title: Regulation of cytochrome P450IIC12 expression by interleukin-1 alpha, interleukin-6, and dexamethasone.
abstract: During the acute phase response to bacterial endotoxin in rats, hepatic levels of cytochrome P450IIC12 [AH, reduced flavoprotein:oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] (P450IIC12) apoenzyme and mRNA are suppressed. We set out to determine the effects of potential humoral mediators of inflammation on the expression of P450IIC12 in female rats. A single injection of 12,000 or 60,000 units of interleukin-1 alpha had no effect on total cytochrome P450 content or P450IIC12 mRNA measured 12 hr later, although P450IIC12 apoenzyme was slightly but significantly increased by the higher dose. In the second experiment, animals were given dexamethasone (100 micrograms/kg at -30 min), interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr), or both and were sacrificed at 12 hr. Treatment with interleukin-1 alpha alone significantly suppressed total cytochrome P450, P450IIC12 apoenzyme, and P450IIC12 mRNA to 77, 53, and 65% of control levels, respectively; beta-actin mRNA was significantly increased (206% of control levels). Treatment with dexamethasone alone suppressed total cytochrome P450 and P450IIC12 mRNA (73% of controls) but did not significantly affect P450IIC12 apoenzyme measured 12.5 hr later. Again, beta-actin mRNA was increased. When both interleukin-1 alpha and dexamethasone were given, total cytochrome P450 and P450IIC12 mRNA (43% of controls) were suppressed, and beta-actin mRNA was significantly increased. In the third experiment, animals were injected at 0 and 12 hr with dexamethasone (83 micrograms/kg), interleukin-6 (33 micrograms/kg), or both. Interleukin-6 alone did not significantly affect total cytochrome P450 or P450IIC12 apoenzyme or mRNA. Dexamethasone alone suppressed P450IIC12 apoenzyme and mRNA (to 52 and 41%, respectively, of controls). Treatment with both interleukin-6 and dexamethasone significantly suppressed total cytochrome P450 and P450IIC12 apoenzyme and mRNA; suppression of P450IIC12 mRNA (to 16% of controls) was greater than with dexamethasone alone. No change in the transcription rate of CYP2C12 was observed 24 hr after initiation of treatment with dexamethasone (83 micrograms/kg at 0 and 12 hr) or 12 hr after initiation of treatment with interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr). We conclude that, in this model, interleukin-1 alpha and glucocorticoids are important mediators of the suppression of hepatic P450IIC12 expression during inflammation. Interleukin-6 was not as potent, but it did potentiate the effects of dexamethasone. Suppression of P450IIC12 expression by dexamethasone and interleukin-1 alpha appeared to be mediated at a pretranslational level, but the possibility of a transcriptional effect needs to be further investigated.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: K
authors.initials: K
authors.lastname: Wright
authors.forename: E T
authors.initials: ET
authors.lastname: Morgan
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015151:Immunoblotting; D007249:Inflammation / Q000201:enzymology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D009841:Oligonucleotides; D011071:Poly T; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000199:Actins; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D009841:Oligonucleotides; D012333:RNA, Messenger; D011071:Poly T; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases