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Research ArticleArticle

Inhibition of Heme Oxygenase-1 Partially Reverses the Arsenite-Mediated Decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 Catalytic Activity in Isolated Rat Hepatocytes

Anwar Anwar-Mohamed, Lars-Oliver Klotz and Ayman O. S. El-Kadi
Drug Metabolism and Disposition March 2012, 40 (3) 504-514; DOI: https://doi.org/10.1124/dmd.111.042564
Anwar Anwar-Mohamed
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Lars-Oliver Klotz
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Ayman O. S. El-Kadi
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Abstract

Heme oxygenase (HO-1), the rate-limiting enzyme in the physiological breakdown of heme, is ubiquitous, and its expression can be increased by arsenite [As(III)], and similar other stimuli that induce cellular oxidative stress. Interestingly, it has been shown that the As(III)-induced HO-1 is inversely correlated with a decrease in cytochromes P450 (P450s) activity; however, the direct role for HO-1 in the inhibition of P450 enzymes remains unknown. Our results showed that As(III) at a concentration of 5 μM decreased the constitutive and inducible expression of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 at the mRNA, protein, and catalytic activity levels. Moreover, As(III) decreased the nuclear accumulation of aryl hydrocarbon receptor (AhR) and pregnane X receptor without increasing their degradation. As(III) also increased the binding of cytosolic AhR to heat shock protein 90 and hepatitis B virus X-associated protein 2. In the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin as an inducer for CYP1A and rifampin as an inducer for CYP3A, As(III) decreased the enzymatic activity of the four P450s more than it decreased their mRNA or protein expression levels. It is noteworthy that treatment with the competitive HO-1 inhibitor, tin-mesoporphyrin, or supplementing external heme partially reversed the As(III)-mediated decrease in activities of the four P450s. In conclusion, the current study provides the first evidence that As(III) decreases CYP1A1, CYP1A2, CYP3A23, and CYP3A2 expression in freshly isolated rat primary hepatocytes. Furthermore, inhibiting the As(III)-mediated induction of HO-1 partially restores the enzymatic activity of these P450s that was initially decreased by As(III), confirming the direct role of HO-1 in the inhibition of P450s.

Footnotes

  • This work was supported by Natural Sciences and Engineering Research Council of Canada [Discovery Grant RGPIN 250139-07]. A.A.-M. is the recipient of an Alberta Innovates Technology Futures Graduate Scholarship.

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

    http://dx.doi.org/10.1124/dmd.111.042564.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    AhR
    aryl hydrocarbon receptor
    Hsp90
    heat shock protein 90
    XAP2
    hepatitis B virus X-associated protein 2
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    ARNT
    aryl hydrocarbon receptor nuclear translocator
    XRE
    xenobiotic response element
    PXR
    pregnane X receptor
    CAR
    constitutive androstane receptor
    Rif
    rifampin
    RXRα
    retinoid X receptor α
    As(III)
    arsenite
    HO-1
    heme oxygenase-1
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    DMEM
    Dulbecco's modified Eagle's medium
    DFB
    [3-[(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one]
    DFH
    [3-hydroxy-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one]
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    DMSO
    dimethylsulfoxide
    PCR
    polymerase chain reaction
    RT-PCR
    reverse transcription-polymerase chain reaction
    EROD
    7-ethoxyresorufin O-deethylase
    MROD
    7-methoxyresorufin O-deethylase
    EMSA
    electrophoretic mobility shift assay
    SnMP
    tin mesoporphyrin
    CT
    cycle threshold.

  • Received August 29, 2011.
  • Accepted December 8, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

INHIBITION OF CYTOCHROME P450s BY As(III)

Anwar Anwar-Mohamed, Lars-Oliver Klotz and Ayman O. S. El-Kadi
Drug Metabolism and Disposition March 1, 2012, 40 (3) 504-514; DOI: https://doi.org/10.1124/dmd.111.042564

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Research ArticleArticle

INHIBITION OF CYTOCHROME P450s BY As(III)

Anwar Anwar-Mohamed, Lars-Oliver Klotz and Ayman O. S. El-Kadi
Drug Metabolism and Disposition March 1, 2012, 40 (3) 504-514; DOI: https://doi.org/10.1124/dmd.111.042564
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