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Journal of Pharmacology and Experimental Therapeutics

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OtherDRUG METABOLISM AND DISPOSITION

Differential Inductive and Suppressive Effects of Endotoxin and Particulate Irritants on Hepatic and Renal Cytochrome P-450 Expression

Marion B. Sewer, Dennis R. Koop and Edward T. Morgan
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1445-1454;
Marion B. Sewer
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Dennis R. Koop
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Edward T. Morgan
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Abstract

Inflammatory stimuli such as bacterial lipopolysaccharide (LPS) have been shown to down-regulate the mRNA and protein expression of hepatic cytochrome P-450 (P-450) isozymes 2C11, 2C12, 2E1 and 3A2 and to induce the mRNA expression of the P-450 4A subfamily. In this study, we examined the effects of irritants on the hepatic and renal expression of P-450 2C11, 2E1 and 3A2 and the 4A subfamily in the rat. Fischer 344 rats were administered doses of SiO2 (Celite), BaSO4, kaolin and LPS intraperitoneally and killed after different times for hepatic and renal RNA and microsome isolation. The administration of each irritant was found to suppress hepatic P-450 2C11 mRNA and protein and to induce P-450 4A1, 4A2 and 4A3 mRNA expression while having no significant effect on P-450 2E1 or 3A2. P-450 4A2, 4A3 and 2E1 mRNAs were all induced in the kidney cortices of the irritant- and LPS-treated rats. The effects of BaSO4and SiO2 were found to be dose dependent. Chlorzoxazone-6-hydroxylase activity increased in the kidneys of irritant-treated rats, which is consistent with an increased expression of P-450 2E1. All irritants were found to induce the mRNA for the acute-phase protein fibrinogen; however, in contrast to LPS treatment, none of the irritants that were tested induced hepatic inducible nitric oxide synthase mRNA expression. These findings demonstrate the induction of renal P-450 isozymes after irritant and LPS administration. The findings of this study also suggest that different inflammatory stimuli affect the individual P-450 isozymes differentially.

Footnotes

  • Send reprint requests to: Dr. Edward T. Morgan, Department of Pharmacology, Emory University School of Medicine, 5119 Rollins Research Center, Atlanta, GA 30322-3090. E-mail:etmorga{at}bimcore.emory.edu

  • ↵1 This work was supported by National Institute of General Medical Sciences Grants GM46897 and GM/OD53093 (E.T.M.), National Institute on Alcohol Abuse and Alcoholism Grant AA08608 (D.R.K.) and a Howard Hughes Predoctoral Fellowship (M.B.S.). This work was presented in part at the American Society for Biochemistry and Molecular Biology Conference in May 1995 (San Francisco, CA).

  • ↵2 M. B. Sewer and E. T. Morgan, unpublished observations.

  • Abbreviations:
    LPS
    lipopolysaccharide
    iNOS
    inducible nitric oxide synthase
    IL
    interleukin
    TNF-α
    tumor necrosis factor-α
    IFN-γ
    interferon-γ
    AGP
    α1-acid glycoprotein
    PPAR
    peroxisome proliferator activated receptor
    NO
    nitric oxide
    • Received August 12, 1996.
    • Accepted November 25, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherDRUG METABOLISM AND DISPOSITION

Differential Inductive and Suppressive Effects of Endotoxin and Particulate Irritants on Hepatic and Renal Cytochrome P-450 Expression

Marion B. Sewer, Dennis R. Koop and Edward T. Morgan
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1445-1454;

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OtherDRUG METABOLISM AND DISPOSITION

Differential Inductive and Suppressive Effects of Endotoxin and Particulate Irritants on Hepatic and Renal Cytochrome P-450 Expression

Marion B. Sewer, Dennis R. Koop and Edward T. Morgan
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1445-1454;
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