Vol. 300, Issue 3, 824-830, March 2002

Enhanced Induction of Cytochrome P450 Enzymes and CAR Binding in TNF (p55^//p75^/) Double Receptor Knockout Mice Following Phenobarbital Treatment

Peter J. Van Ess, Mark P. Mattson and Robert A. Blouin

College of Pharmacy, Division of Pharmaceutical Sciences (P.V.E., R.A.B.) and Sanders-Brown Research Center on Aging (M.P.M), University of Kentucky, Lexington, Kentucky; and Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center (M.P.M.) and Department of Neuroscience, Johns Hopkins University School of Medicine (M.P.M), Baltimore, Maryland

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 (TNF) response. To test the hypothesis that endogenous TNF 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 -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 TNF signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNF signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation.