Down-regulation of P4501A1 and P4501A2 mRNA expression in isolated hepatocytes by oxidative stress

We have previously shown that the inflammatory mediator interleukin-1 suppressed transcription of CYP1A1 and CYP1A2 mRNAs (Barker, C.W., Fagan, J.B., and Pasco, D.S. (1992) J. Biol. Chem. 267, 8050-8055). Since many of the actions of inflammatory mediators are mimicked by oxidative stress, we treate...

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Veröffentlicht in:The Journal of biological chemistry 1994-02, Vol.269 (6), p.3985-3990
Hauptverfasser: BARKER, C. W, FAGAN, J. B, PASCO, D. S
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FAGAN, J. B
PASCO, D. S
description We have previously shown that the inflammatory mediator interleukin-1 suppressed transcription of CYP1A1 and CYP1A2 mRNAs (Barker, C.W., Fagan, J.B., and Pasco, D.S. (1992) J. Biol. Chem. 267, 8050-8055). Since many of the actions of inflammatory mediators are mimicked by oxidative stress, we treated isolated hepatocytes with 0.25-1.0 mM H2O2 to determine whether expression of these genes is also modulated by oxidative stress. Inducer-dependent accumulation of CYP1A1 and CYP1A2 mRNAs were maximally reduced approximately 50 and 70%, respectively, by 1.0 mM H2O2. Run-on transcription analysis suggested that the effect of H2O2 was mediated transcriptionally. The reduction in CYP1A mRNA levels was not due to a reduction in the levels of all mRNAs due to some general toxic effect since H2O2 did not reduce glyceraldehyde-3-phosphate dehydrogenase, alpha-tubulin, beta-fibrinogen, or albumin mRNA levels, and did not increase lactate dehydrogenase released into the medium. Insulin-mimicked H2O2 action, reducing the expression of both mRNAs, and N-acetylcysteine, which increases intracellular glutathione levels, completely reversed the insulin effect on both mRNAs and the H2O2 effect on CYP1A1 mRNA, but only partially reversed the H2O2 effect on CYP1A2 mRNA. This study indicates that the CYP1A1 and CYP1A2 genes are responsive to oxidative stress and that the majority of this responsiveness can be modified by cellular redox potential.
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Psychology ; Gene Expression ; Genes, jun ; Glutathione - metabolism ; Hydrogen Peroxide - pharmacology ; Insulin - pharmacology ; Liver - metabolism ; Male ; Molecular and cellular biology ; Molecular genetics ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - genetics ; Stress, Physiological - enzymology ; Transcription, Genetic - drug effects ; Transcription. Transcription factor. Splicing. 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W</creatorcontrib><creatorcontrib>FAGAN, J. B</creatorcontrib><creatorcontrib>PASCO, D. S</creatorcontrib><title>Down-regulation of P4501A1 and P4501A2 mRNA expression in isolated hepatocytes by oxidative stress</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>We have previously shown that the inflammatory mediator interleukin-1 suppressed transcription of CYP1A1 and CYP1A2 mRNAs (Barker, C.W., Fagan, J.B., and Pasco, D.S. (1992) J. Biol. Chem. 267, 8050-8055). Since many of the actions of inflammatory mediators are mimicked by oxidative stress, we treated isolated hepatocytes with 0.25-1.0 mM H2O2 to determine whether expression of these genes is also modulated by oxidative stress. Inducer-dependent accumulation of CYP1A1 and CYP1A2 mRNAs were maximally reduced approximately 50 and 70%, respectively, by 1.0 mM H2O2. Run-on transcription analysis suggested that the effect of H2O2 was mediated transcriptionally. 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This study indicates that the CYP1A1 and CYP1A2 genes are responsive to oxidative stress and that the majority of this responsiveness can be modified by cellular redox potential.</description><subject>Animals</subject><subject>Benzoflavones - pharmacology</subject><subject>beta-Naphthoflavone</subject><subject>Biological and medical sciences</subject><subject>Cell Survival - drug effects</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression</subject><subject>Genes, jun</subject><subject>Glutathione - metabolism</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Insulin - pharmacology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Molecular and cellular biology</subject><subject>Molecular genetics</subject><subject>Oxidation-Reduction</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA, Messenger - genetics</subject><subject>Stress, Physiological - enzymology</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transcription. Transcription factor. Splicing. 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Psychology</topic><topic>Gene Expression</topic><topic>Genes, jun</topic><topic>Glutathione - metabolism</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Insulin - pharmacology</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Molecular and cellular biology</topic><topic>Molecular genetics</topic><topic>Oxidation-Reduction</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA, Messenger - genetics</topic><topic>Stress, Physiological - enzymology</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transcription. Transcription factor. Splicing. Rna processing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BARKER, C. W</creatorcontrib><creatorcontrib>FAGAN, J. B</creatorcontrib><creatorcontrib>PASCO, D. 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Inducer-dependent accumulation of CYP1A1 and CYP1A2 mRNAs were maximally reduced approximately 50 and 70%, respectively, by 1.0 mM H2O2. Run-on transcription analysis suggested that the effect of H2O2 was mediated transcriptionally. The reduction in CYP1A mRNA levels was not due to a reduction in the levels of all mRNAs due to some general toxic effect since H2O2 did not reduce glyceraldehyde-3-phosphate dehydrogenase, alpha-tubulin, beta-fibrinogen, or albumin mRNA levels, and did not increase lactate dehydrogenase released into the medium. Insulin-mimicked H2O2 action, reducing the expression of both mRNAs, and N-acetylcysteine, which increases intracellular glutathione levels, completely reversed the insulin effect on both mRNAs and the H2O2 effect on CYP1A1 mRNA, but only partially reversed the H2O2 effect on CYP1A2 mRNA. 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subjects Animals
Benzoflavones - pharmacology
beta-Naphthoflavone
Biological and medical sciences
Cell Survival - drug effects
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Fundamental and applied biological sciences. Psychology
Gene Expression
Genes, jun
Glutathione - metabolism
Hydrogen Peroxide - pharmacology
Insulin - pharmacology
Liver - metabolism
Male
Molecular and cellular biology
Molecular genetics
Oxidation-Reduction
Rats
Rats, Sprague-Dawley
RNA, Messenger - genetics
Stress, Physiological - enzymology
Transcription, Genetic - drug effects
Transcription. Transcription factor. Splicing. Rna processing
title Down-regulation of P4501A1 and P4501A2 mRNA expression in isolated hepatocytes by oxidative stress
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