Elsevier

Biochemical Pharmacology

Volume 47, Issue 7, 29 March 1994, Pages 1187-1195
Biochemical Pharmacology

Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells

https://doi.org/10.1016/0006-2952(94)90391-3Get rights and content

Abstract

The effects of interleukin-6 (IL-6), the major inducer of the acute-phase reaction, on the expression of cytochrome P450IA1 (CYPIA1) were examined using human HepG2 hepatoma cells. Treatment of cells with IL-6 decreased the level of 3-methylhcholanthrene-induced CYPIA1 protein and its mRNA. Nuclear runoff analysis revealed that the effect of IL-6 was largely transcriptional. IL-6 treatment of HepG2 cells increased mRNA for microsomal heme oxygenase, the rate-limiting enzyme in heme.catabolism, suggesting that the suppressive effect of IL-6 on CYPIA1 mRNA may be due to a loss of heme. Consistent with this hypothesis, simultaneous treatment of cells with Sn-mesoporphyrin, an inhibitor of heme oxygenase, prevented the IL-6-mediated suppression of CYPIA1. These findings suggest that the suppression of P450IA1 mRNA by IL-6 appears to occur, at least in part, from the decline in free heme content as a result of the induction of heme oxygenase. Our results raise the possibility that other physiological as well as environmental stimuli which affect cellular heme concentrations may also modulate the expression of P450s.

References (51)

  • G.S. Drummond et al.

    Reduction of the C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesophorphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism

    Arch Biochem Biophys

    (1987)
  • M. Ishikawa et al.

    Endotoxin- and inflammation-induced depression of the hepatic drug metabolism in rats

    Jpn J Pharmacol

    (1991)
  • S.I. Shedlofsky et al.

    Interleukin-1 (IL-1) depresses cytochrome P450 levels and activities in mice

    Life Sci

    (1987)
  • Y.L. Chen et al.

    Effects of interleukin-6 on cytochrome p450-dependent mixed-function oxidases in the rat

    Biochem Pharmacol

    (1992)
  • P. Ghezzi et al.

    Recombinant tumor necrosis factor depresses cytochrome P450-dependent microsomal drug metabolism in mice

    Biochem Biophys Res Commun

    (1986)
  • K. Wright et al.

    Transcriptional and post-transcriptional suppression of P450IIC11 and P450IIC12 by inflammation

    FEBS Lett

    (1990)
  • C.W. Barker et al.

    Interleukin-1β suppresses the induction of P4501A1 and P4501A2 mRNAs in isolated hepatocytes

    J Biol Chem

    (1992)
  • S. Granick et al.

    Effects by heme, insulin, and serum albumin on heme and protein synthesis in chick embryo liver cells cultured in a chemically defined medium, and a spectrofluorometric assay for porphyrin composition

    J Biol Chem

    (1975)
  • H. Ravishankar et al.

    Regulation of cytochrome P-450 gene expression: Studies with a cloned probe

    J Biol Chem

    (1985)
  • G. Jayarama Bhat et al.

    Heme regulates cytochrome P-450 gene transcription elongation

    Biochem Biophys Res Commun

    (1988)
  • V. Poli et al.

    IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP

    Cell

    (1990)
  • S. Shibahara et al.

    Transcriptional control of rat heme oxygenase by heat shock

    J Biol Chem

    (1987)
  • D.W. Nebert et al.

    P450 genes: Structure, evolution and regulation

    Annu Rev Biochem

    (1987)
  • F.J. Gonzalez

    The molecular biology of cytochrome P450s

    Pharmacol Rev

    (1989)
  • S. Sassa et al.

    Genetic, metabolic, and biochemical aspects of the porphyrias

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