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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

The Effects of Ethanol and Acetaldehyde on the Metabolism of Prostaglandin E2 and Leukotriene B4 in Isolated Rat Hepatocytes

Joseph A. Hankin, Carl E. Clay and Robert C. Murphy
Journal of Pharmacology and Experimental Therapeutics April 1998, 285 (1) 155-161;
Joseph A. Hankin
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Carl E. Clay
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Robert C. Murphy
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Abstract

The effects of ethanol and acetaldehyde on the metabolism of leukotriene B4 (LTB4) and PGE2 were investigated in isolated cultures of rat hepatocytes. LTB4undergoes initial cytochrome P450-dependent ω-oxidation leading to the principal metabolites 20-hydroxy-LTB4, 20-carboxy-LTB4 and the ω/β-oxidation product 18-carboxy-LTB4. The addition of low concentrations of ethanol (25 mM) dramatically changes the relative amounts of these metabolite products by inhibiting the alcohol dehydrogenase-mediated oxidation of 20-hydroxy-LTB4. Addition of acetaldehyde to the incubation, up to 1 mM, had no significant effect on overall metabolism or distribution of metabolites. Above 1 mM acetaldehyde, β-oxidation of LTB4 was inhibited. Thus the effect of ethanol on the metabolism of LTB4 appears to be due to ethanol itself and not to secondary effects from the metabolic transformation of ethanol to acetaldehyde in the cells. PGE2 is metabolized in isolated rat hepatocytes to produce chain-shortened products of β-oxidation characterized as dinor-PGE1, dinor-PGE2, tetranor-PGE1, tauro-dinor-PGE1 and tauro-dinor-PGE2. Low concentrations of ethanol (25 mM) were found to increase the relative concentration of dinor-PGE1 in the metabolic distribution, with a corresponding decrease in concentration of tetranor-PGE1. The amount of dinor-PGE2 that was produced remained relatively unchanged in response to increasing concentrations of ethanol. Acetaldehyde concentrations from 0.1 mM to 1 mM did not affect metabolite distribution or the overall magnitude of PGE2metabolism. Concentrations of acetaldehyde higher than 1 mM decreased all β-oxidation metabolites. Ethanol, at physiologically relevant concentrations, could alter eicosanoid metabolism in the liver by inhibiting LTB4 metabolism and altering that of PGE2.

Footnotes

  • Send reprint requests to: Robert C. Murphy, Ph.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206.

  • ↵1 This work was supported in part by a grant from the National Institutes of Health (AA09468).

  • Abbreviations:
    LTB4
    leukotriene B4
    HBSS
    Hank’s balanced salt solution
    BSA
    bovine serum albumin
    LC/MS
    liquid chromatography/mass spectrometry
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MRM
    multiple reaction monitoring
    mAU
    milliabsorbancy unit
    • Received August 13, 1997.
    • Accepted December 9, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 1
1 Apr 1998
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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

The Effects of Ethanol and Acetaldehyde on the Metabolism of Prostaglandin E2 and Leukotriene B4 in Isolated Rat Hepatocytes

Joseph A. Hankin, Carl E. Clay and Robert C. Murphy
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 155-161;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

The Effects of Ethanol and Acetaldehyde on the Metabolism of Prostaglandin E2 and Leukotriene B4 in Isolated Rat Hepatocytes

Joseph A. Hankin, Carl E. Clay and Robert C. Murphy
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 155-161;
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