Nitric oxide-independent suppression of P450 2C11 expression by interleukin-1beta and endotoxin in primary rat hepatocytes.
Hepatic expression of multiple cytochrome P450 genes is suppressed in the livers of rats undergoing an inflammatory response. Nitric oxide (NO) released during inflammation has been implicated in the decreased activities and expression of several cytochrome P450 isozymes. We examined the role of cytokine-mediated NO release on cytochrome P450 2C11 expression in rat hepatocytes cultured on Matrigel. Lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha), but not interferon-gamma (IFN-gamma), suppressed the expression of P450 2C11 mRNA. Neither IL-6 nor IFN-gamma caused NO release into the medium or induction of inducible nitric oxide synthase (iNOS) mRNA. IL-1beta and LPS were the most effective in causing NO release and iNOS induction, and in down-regulating P450 2C11 mRNA expression. Combinations of the cytokines, IFN-gamma, and LPS produced an additive release of NO but did not synergize to further suppress P450 2C11 mRNA. To investigate the role of NO in the IL-1beta- or LPS-mediated suppression of P450 2C11, N-monomethyl-L-arginine (NMA) was administered at concentrations ranging from 30 to 300 microM. Three hundred micromolar NMA returned NO release back to control levels, but did not affect the IL-1beta- or LPS-mediated down-regulation of P450 2C11 mRNA or protein expression. Our results suggest that NO is not required for IL-1beta- or LPS-mediated down-regulation of P450 2C11 expression in cultured hepatocytes.
Sewer
M B
MB
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090, U.S.A.
Morgan
E T
ET
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C036911:N(G)-monoethylarginine; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D013250:Steroid Hydroxylases; D019001:Nitric Oxide Synthase; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase