Effect of interleukin 6 on phenobarbital induction of cytochrome P-450IIB in cultured rat hepatocytes

Williams, Joseph F.; Bement, William J.; Sinclair, Jacqueline F.; Sinclair, Peter R.

doi:10.1016/0006-291x(91)90998-m

Cited by 53 publications

(13 citation statements)

References 22 publications

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“…Consistent with the negative influence of proinflammatory cytokines on constitutive P450 expression, these same cytokines have been shown in a number of cultured hepatocyte investigations to significantly blunt PB induction of CYP2B and CYP3A (Williams et al, 1991;Abdel-Razzak et al, 1995;Clark et al, 1995Clark et al, , 1996. In rat hepatocytes, TNF␣, IL-1␤, IL-6, and interferon have all been shown to inhibit PB induction of CYP2B and CYP3A (Williams et al, 1991;Abdel-Razzak et al, 1995;Clark et al, 1995Clark et al, , 1996Pascussi et al, 2000). The recent discovery and characterization of the "orphan" nuclear receptor CAR, a critical transcriptional regulator of CYP2B gene expression, provides a mechanism by which cytokines may alter PB induction of CYP2B.…”

supporting

confidence: 65%

“…Phenobarbital (PB) is a well studied inducer of a number of P450 subfamilies, the two most significant being the 50-to 100-fold induction of CYP2B and the 2-to 3-fold induction of CYP3A activity in rodents (for review see Waxman and Azaroff, 1992). Consistent with the negative influence of proinflammatory cytokines on constitutive P450 expression, these same cytokines have been shown in a number of cultured hepatocyte investigations to significantly blunt PB induction of CYP2B and CYP3A (Williams et al, 1991;Abdel-Razzak et al, 1995;Clark et al, 1995Clark et al, , 1996. In rat hepatocytes, TNF␣, IL-1␤, IL-6, and interferon have all been shown to inhibit PB induction of CYP2B and CYP3A (Williams et al, 1991;Abdel-Razzak et al, 1995;Clark et al, 1995Clark et al, , 1996Pascussi et al, 2000).…”

mentioning

confidence: 96%

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

Ess

Mattson

Blouin

2002

J Pharmacol Exp Ther

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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 Ϫ/Ϫ /p75 Ϫ/Ϫ ) 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 Ͻ 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.

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supporting

confidence: 65%

mentioning

confidence: 96%

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

Ess

Mattson

Blouin

2002

J Pharmacol Exp Ther

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“…The suppressive effects of thyroid hormone also contribute to the maintenance of 2B at a low level in uninduced rats (Murayama et al, 1991), just as thyroid hormone suppresses the basal expression of the PB-inducible 3A2 mRNA (Waxman et al, 1990a;Ram & Waxman, 1991). The PB-inducibility of 2B1 and 2B2 is also inhibited by interleukin 6, a major mediator of hepatic acute phase reaction (Williams et al, 1991). Aging of male rats is associated with a general demasculinization of 1992 hepatic P-450 expression (e.g.…”

Section: B1 and 2b2 Proteinsmentioning

confidence: 95%

Phenobarbital induction of cytochrome P-450 gene expression

Waxman

Azaroff

1992

Biochemical Journal

496

265

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“…The suppression of the constitutive expression of different isoforms from CYP1-CYP3 families by IL6 has been documented in hepatocyte cultures of different mammals including pigs (Kleine et al, 2008), rabbits (Kourylko et al, 2006), rats (Williams et al, 1991;Chen et al, 1995), and humans (Abdel-Razzak et al, 1993;Muntané-Relat et al, 1995;Aitken and Morgan, 2007). There is also evidence that IL6 has significant in vivo roles in rodents.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Hepatic Cytochrome P450s byCitrobacter rodentiumInfection in Interleukin-6- and Interferon-γ-Null Mice

Nyagode¹,

Lee²,

Morgan³

2010

J Pharmacol Exp Ther

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After infection with Citrobacter rodentium, murine hepatic cytochrome P450 (P450) mRNAs are selectively regulated. Several serum proinflammatory cytokines are elevated, the most abundant being interleukin-6 (IL6). To elucidate the role of cytokines in the regulation of P450s during infection, we orally infected wild-type, IL6(Ϫ/Ϫ), or interferon-␥(Ϫ/Ϫ) [IFN␥(Ϫ/Ϫ)] female C57BL/6J mice with C. rodentium and analyzed hepatic P450 expression 7 days later. The majority of P450 mRNAs were equally affected by infection in each genotype, indicating that IL6 and IFN␥ are not the primary mediators of P450 downregulation in this disease model. The down-regulation of CYP3A11 and CYP3A13 and induction of CYP2D9 mRNAs were attenuated in the IL6(Ϫ/Ϫ) mice, suggesting a role of IL6 in the regulation of only these P450s. Similar evidence implicated IFN␥ in the regulation of CYP2D9, CYP2D22, CYP3A11, CYP3A25, and CYP4F18 mRNAs in C. rodentium infection and CYP2B9, CYP2D22, and CYP2E1 in the bacterial lipopolysaccharide model of inflammation. This is the first indication of an in vivo role for IFN␥ in hepatic P450 regulation in disease states. The deficiency of IL6 or IFN␥ affected serum levels of the other cytokines. Moreover, experiments in cultured hepatocytes demonstrated that tumor necrosis factor ␣ (TNF␣) is the most potent and efficacious of the cytokines tested in the regulation of murine P450 expression. It is therefore possible that part of the IFN␥(Ϫ/Ϫ) and IL6(Ϫ/Ϫ) phenotypes could be attributed to the reduced levels of TNF␣ and part of the IFN␥(Ϫ/Ϫ) phenotype could be caused by reduced levels of IL6.

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Effect of interleukin 6 on phenobarbital induction of cytochrome P-450IIB in cultured rat hepatocytes

Cited by 53 publications

References 22 publications

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

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

Phenobarbital induction of cytochrome P-450 gene expression

Modulation of Hepatic Cytochrome P450s byCitrobacter rodentiumInfection in Interleukin-6- and Interferon-γ-Null Mice

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Effect of interleukin 6 on phenobarbital induction of cytochrome P-450IIB in cultured rat hepatocytes

Cited by 53 publications

References 22 publications

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

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

Phenobarbital induction of cytochrome P-450 gene expression

Modulation of Hepatic Cytochrome P450s byCitrobacter rodentiumInfection in Interleukin-6- and Interferon-γ-Null Mice

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

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