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Research ArticleArticle

IMPACT OF TRANSCRIPTION FACTOR PROFILE AND CHROMATIN CONFORMATION ON HUMAN HEPATOCYTE CYP3A GENE EXPRESSION

Anna Phillips, Steve R. Hood, G. Gordon Gibson and Nick J. Plant
Drug Metabolism and Disposition February 2005, 33 (2) 233-242; DOI: https://doi.org/10.1124/dmd.104.001461
Anna Phillips
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Steve R. Hood
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G. Gordon Gibson
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Nick J. Plant
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Abstract

Recent data have made it increasingly clear that the gene expression profile of a cell system, and its alteration in response to external stimuli, is highly dependent on both the higher order chromatin structure of the genome and the interaction of gene products in interpreting stimuli. To further explore this phenomenon, we have examined the role of both of these factors in controlling xenobiotic-mediated gene expression changes in primary and transformed human hepatocytes (HuH7). Using quantitative polymerase chain reaction, expression levels of several transcription factors implicated in the liver-specific regulation of the CYP3A gene family were examined in human adult and fetal liver RNA samples. These expression profiles were then compared with those obtained from both primary and transformed human hepatocytes, showing that, in general, cultured cells exhibit a distinct profile compared with either the fetal or adult samples. Transcriptome profiles before and after exposure to the CYP3A transcriptional activators rifampicin, dexamethasone, pregnane-16α-carbonitrile, and phenobarbital were subsequently examined. Whereas exposure to these compounds elicited a dose-dependent increase in CYP3A transcription in primary hepatocytes, no alteration in expression levels was observed for the hepatoma cell line HuH7. Alteration in the expression levels of pregnane X receptor and chicken ovalbumin upstream promoter transcription factor I, and the disruption of higher order chromatin within HuH7 cells altered CYP3A expression and/or activation by xenobiotics toward that observed in primary hepatocytes. These data provide potential roles for these two processes in regulating CYP3A expression in vivo.

Footnotes

  • A.P. was funded by GlaxoSmithKline/Biotechnology and Biological Sciences Research Council.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.001461.

  • ABBREVIATIONS: DME, drug-metabolizing enzyme; ANOVA, analysis of variance; bp, base pair(s); CAR, constitutive androstane receptor; COUP-TFI, chicken ovalbumin upstream promoter transcription factor I; DMSO, dimethyl sulfoxide; GRα, glucocorticoid receptor α; HCA, hierarchical cluster analysis; HNF, hepatic nuclear factor; PCA, principal component analysis; PCN, pregnenalone-16α-carbonitrile; PXR, pregnane X receptor; Q-PCR, quantitative polymerase chain reaction; TSA, trichostatin A.

    • Received July 13, 2004.
    • Accepted October 28, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (2)
Drug Metabolism and Disposition
Vol. 33, Issue 2
1 Feb 2005
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Research ArticleArticle

IMPACT OF TRANSCRIPTION FACTOR PROFILE AND CHROMATIN CONFORMATION ON HUMAN HEPATOCYTE CYP3A GENE EXPRESSION

Anna Phillips, Steve R. Hood, G. Gordon Gibson and Nick J. Plant
Drug Metabolism and Disposition February 1, 2005, 33 (2) 233-242; DOI: https://doi.org/10.1124/dmd.104.001461

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Research ArticleArticle

IMPACT OF TRANSCRIPTION FACTOR PROFILE AND CHROMATIN CONFORMATION ON HUMAN HEPATOCYTE CYP3A GENE EXPRESSION

Anna Phillips, Steve R. Hood, G. Gordon Gibson and Nick J. Plant
Drug Metabolism and Disposition February 1, 2005, 33 (2) 233-242; DOI: https://doi.org/10.1124/dmd.104.001461
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