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Research ArticleArticle

ARSENITE DECREASES CYP3A4 AND RXRα IN PRIMARY HUMAN HEPATOCYTES

Trisha L. Noreault, Vsevolod E. Kostrubsky, Sheryl G. Wood, Ralph C. Nichols, Stephen C. Strom, Heidi W. Trask, Steven A. Wrighton, Ronald M. Evans, Judith M. Jacobs, Peter R. Sinclair and Jacqueline F. Sinclair
Drug Metabolism and Disposition July 2005, 33 (7) 993-1003; DOI: https://doi.org/10.1124/dmd.105.003954
Trisha L. Noreault
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Vsevolod E. Kostrubsky
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Sheryl G. Wood
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Ralph C. Nichols
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Stephen C. Strom
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Heidi W. Trask
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Steven A. Wrighton
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Ronald M. Evans
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Judith M. Jacobs
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Peter R. Sinclair
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Jacqueline F. Sinclair
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Abstract

Arsenic is a naturally occurring, worldwide contaminant implicated in numerous pathological conditions in humans, including cancer and several forms of liver disease. One of the contributing factors to these disorders may be the alteration of cytochrome P450 (P450) levels by arsenic. P450s are involved in the oxidative metabolism and elimination of numerous toxic chemicals. CYP3A4, a major P450 in humans, is involved in the metabolism of half of all currently used drugs. Acute exposure to arsenite decreases the induction of CYP1A1/2 proteins and activities in cultured human hepatocytes, as well as CYP3A23 in cultured rat hepatocytes. Here, in primary cultures of human hepatocytes, we assessed the effects of acute arsenite exposure on CYP3A4 and several transcription factors involved in CYP3A4 expression. The concentrations of arsenite used in these studies were nontoxic to the hepatocytes and failed to elicit an oxidative response. Treatment with arsenite in the presence of CYP3A4 inducers, rifampicin (Rif) or phenobarbital, caused major decreases in CYP3A4 mRNA, protein, and activity. In addition, the levels of CYP3A4 in untreated cells were decreased following arsenite treatment. Transcription of the CYP3A4 gene is primarily regulated by heterodimers of the retinoid X receptor α (RXRα) and the pregnane X receptor (PXR). We found that arsenite failed to affect expression of PXR or the transcription factor Sp1, yet caused a significant decrease in PXR responsiveness to Rif. Arsenite caused a large decrease in nuclear RXRα protein and, to a lesser extent, RXRα mRNA. These results suggest that arsenite inhibits both untreated and induced CYP3A4 transcription in primary human hepatocytes by decreasing the activity of PXR, as well as expression of the nuclear receptor RXRα.

Footnotes

  • This work was supported in part by National Institutes of Health Grant ES10462 (J.S.), the Department of Veterans Affairs, and the Liver Transplant, Procurement, and Distribution System.

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

  • doi:10.1124/dmd.105.003954.

  • ABBREVIATIONS: P450, cytochrome P450; Rif, rifampicin; PB, sodium phenobarbital; RXRα, retinoid X receptor α; PXR, pregnane X receptor; CAR, constitutive androstane/active receptor; As, sodium arsenite; DEX, dexamethasone; FeNTA, ferric nitrilotriacetic acid; SXR, steroid and xenobiotic receptor; MOPS, 3-(N-morpholino)propanesulfonic acid; PCR, polymerase chain reaction; RT-PCR, reverse transcription-PCR; PAGE, polyacrylamide gel electrophoresis; ROS, reactive oxygen species; TBARS, thiobarbituric acid reactive substances; GR, glucocorticoid receptor.

    • Received January 31, 2005.
    • Accepted April 13, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (7)
Drug Metabolism and Disposition
Vol. 33, Issue 7
1 Jul 2005
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Research ArticleArticle

ARSENITE DECREASES CYP3A4 AND RXRα IN PRIMARY HUMAN HEPATOCYTES

Trisha L. Noreault, Vsevolod E. Kostrubsky, Sheryl G. Wood, Ralph C. Nichols, Stephen C. Strom, Heidi W. Trask, Steven A. Wrighton, Ronald M. Evans, Judith M. Jacobs, Peter R. Sinclair and Jacqueline F. Sinclair
Drug Metabolism and Disposition July 1, 2005, 33 (7) 993-1003; DOI: https://doi.org/10.1124/dmd.105.003954

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Research ArticleArticle

ARSENITE DECREASES CYP3A4 AND RXRα IN PRIMARY HUMAN HEPATOCYTES

Trisha L. Noreault, Vsevolod E. Kostrubsky, Sheryl G. Wood, Ralph C. Nichols, Stephen C. Strom, Heidi W. Trask, Steven A. Wrighton, Ronald M. Evans, Judith M. Jacobs, Peter R. Sinclair and Jacqueline F. Sinclair
Drug Metabolism and Disposition July 1, 2005, 33 (7) 993-1003; DOI: https://doi.org/10.1124/dmd.105.003954
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