Enhanced induction of cytochrome P450 enzymes and CAR binding in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice following phenobarbital treatment.
Phenobarbital (PB) is a well characterized inducer of cytochrome P450 (P450) 2B and 3A subfamilies. Several proinflammatory cytokines have been shown to negatively modulate the induction of P450 by PB. In addition, PB is known to elicit an inflammatory mitogenic effect on the liver. To date, no studies have evaluated the PB induction profile of hepatic P450 in the absence of an intact tumor necrosis factor-alpha (TNFalpha) response. To test the hypothesis that endogenous TNFalpha signaling modulates hepatic P450 induction by PB in vivo, PB induction was examined in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice (ko-TNF) and wild-type mice (wt-TNF). CYP2B- and CYP3A-associated activities and protein content were induced to a significantly greater extent (p < 0.05) in ko-TNF mice compared with wt-TNF mice. In parallel with enhanced CYP2B induction, an apparent elevation in the nuclear accumulation of the principal regulatory protein for transcription of CYP2B genes, the constitutively activated receptor (CAR), was detected in ko-TNF nuclear extracts following PB treatment. Additionally, nuclear factor kappa-B binding was induced by PB in wt-TNF mice, but not in ko-TNF mice, indicating that the hepatic inflammatory response following PB treatment differed between wt-TNF and ko-TNF mice. These data demonstrate that endogenous TNFalpha signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNFalpha signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation.
Van Ess
Peter J
PJ
College of Pharmacy, Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Mattson
Mark P
MP
Blouin
Robert A
RA
D000210:Acute-Phase Reaction; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004586:Electrophoresis; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000090702:Constitutive Androstane Receptor; D016328:NF-kappa B; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital