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Research ArticleArticle

INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR α IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER

Takashi Ashino, Takiko Oguro, Seiji Shioda, Reiko Horai, Masahide Asano, Kenji Sekikawa, Yoichiro Iwakura, Satoshi Numazawa and Takemi Yoshida
Drug Metabolism and Disposition July 2004, 32 (7) 707-714; DOI: https://doi.org/10.1124/dmd.32.7.707
Takashi Ashino
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Takiko Oguro
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Seiji Shioda
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Reiko Horai
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Masahide Asano
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Kenji Sekikawa
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Yoichiro Iwakura
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Satoshi Numazawa
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Takemi Yoshida
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Abstract

Bacillus Calmette-Guérin (BCG) and lipopolysaccharide (LPS) are well known potent activators of the cell-mediated immune system and thus lead to the decreases in cytochrome P450 (P450). In this study we used interleukin (IL)-1α/β, IL-6, or tumor necrosis factor α (TNFα) knockout (KO) mice to investigate how each cytokine is involved in P450 down-regulation, especially CYP3A11 and 2C29. BCG (40 mg/kg) was found to reduce both CYP3A11 and 2C29 mRNAs at 24 h after treatment in IL-1α/β KO mice in a manner similar to that seen in wild-type mice. CYP3A11 mRNA, but not CYP2C29 mRNA, was significantly decreased by BCG treatment in the TNFα KO mice, although the decrease was less than that of wild-type or IL-1α/β KO mice. In contrast, BCG showed no significant effect on CYP3A11 and 2C29 mRNAs in IL-6 KO mice. On the other hand, LPS was able to decrease CYP3A11 and 2C29 mRNA levels in all of the cytokine KO mice and markedly increased systemic levels of TNFα; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNFα are likely to be major factors involved in the down-regulation of CYP3A11 and 2C29 mRNAs in mice. In addition, there exist differences in the amount and/or kind of cytokines released by BCG or LPS, the latter being more potent than the former. This will be a possible reason for differential capability of P450 down-regulation between BCG and LPS.

Footnotes

  • A part of this study was supported by a grant-in-aid from the Ministry of Education, Science and Culture, Japan.

  • ABBREVIATIONS: P450, cytochrome P450; IL, interleukin; BCG, bacillus Calmette-Guérin; LPS, lipopolysaccharide; TNF, tumor necrosis factor; IFN, interferon; KO, knockout; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; PAGE, polyacrylamide gel electrophoresis; HPLC, high-performance liquid chromatography; HO, heme oxygenase.

    • Received December 12, 2003.
    • Accepted March 23, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (7)
Drug Metabolism and Disposition
Vol. 32, Issue 7
1 Jul 2004
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INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR α IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER
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Research ArticleArticle

INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR α IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER

Takashi Ashino, Takiko Oguro, Seiji Shioda, Reiko Horai, Masahide Asano, Kenji Sekikawa, Yoichiro Iwakura, Satoshi Numazawa and Takemi Yoshida
Drug Metabolism and Disposition July 1, 2004, 32 (7) 707-714; DOI: https://doi.org/10.1124/dmd.32.7.707

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Research ArticleArticle

INVOLVEMENT OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR α IN CYP3A11 AND 2C29 DOWN-REGULATION BY BACILLUS CALMETTE-GUÉRIN AND LIPOPOLYSACCHARIDE IN MOUSE LIVER

Takashi Ashino, Takiko Oguro, Seiji Shioda, Reiko Horai, Masahide Asano, Kenji Sekikawa, Yoichiro Iwakura, Satoshi Numazawa and Takemi Yoshida
Drug Metabolism and Disposition July 1, 2004, 32 (7) 707-714; DOI: https://doi.org/10.1124/dmd.32.7.707
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