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Research ArticleArticle

Animal Models of Acute Moderate Hypoxia Are Associated with a Down-Regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and Up-Regulation of CYP3A6 and P-glycoprotein in Liver

Caroline Fradette, Joëlle Batonga, Shirley Teng, Micheline Piquette-Miller and Patrick du Souich
Drug Metabolism and Disposition May 2007, 35 (5) 765-771; DOI: https://doi.org/10.1124/dmd.106.013508
Caroline Fradette
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Joëlle Batonga
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Shirley Teng
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Micheline Piquette-Miller
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Patrick du Souich
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Abstract

In humans, indirect evidence suggests that hypoxia reduces the rate of biotransformation of drugs cleared by cytochrome P450 (P450) subfamilies CYP1A, 2B, and 2C. The aim of this study was to assess whether acute moderate hypoxia modulates the expression of CYP2B4, 2C5, and 2C16 in vivo, and to determine whether the changes in hepatic P450 are conveyed by serum mediators. Moreover, because hypoxia increases the expression of P-glycoprotein in vitro, we examined whether in vivo acute moderate hypoxia modulates the expression of several membrane transporters in the liver. Rabbits and rats were exposed to a fractional concentration of oxygen of 8% for 48 h to generate a stable arterial partial pressure of O2 of 34 ± 1 mm Hg. Compared with rabbits breathing room air, hypoxia in rabbits reduced the amount of CYP1A1, 1A2, 2B4, 2C5, and 2C16 proteins and increased the expression of CYP3A6. Sera of rabbits with hypoxia were fractionated by size exclusion chromatography, the fractions were tested for their ability to modify the expression of P450 isoforms, and serum mediators were identified through neutralization experiments. The serum mediators responsible for the down-regulation of P450 isoforms were interferon-γ, interleukin-1β (IL-1β), and IL-2. In vivo, in rats, hypoxia increased the mRNA and protein expression of P-glycoprotein but did not affect the mRNA of breast cancer resistance protein and organic anion-transporting polypeptide 2. It is concluded that in vivo, hypoxia down-regulates rabbit hepatic CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulates CYP3A6. CYP3A11 and P-glycoprotein were up-regulated in the livers of hypoxic rats.

Footnotes

  • Supported by a grant from the Canadian Institutes of Health Research (MOP-43925).

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

  • doi:10.1124/dmd.106.013508.

  • ABBREVIATIONS: FiO2, fractional concentration of inspired O2; AhR, aryl hydrocarbon receptor; AP-1, activator protein-1; Arnt, aryl hydrocarbon receptor nuclear translocator; BCRP, breast cancer resistance protein; Epo, erythropoietin; HCONT, hepatocytes from control rabbits; HHYPO, hepatocytes from rabbits with hypoxia; HIF-1, hypoxia-inducible factor 1 transcriptional activator; HPLC, high performance liquid chromatography; IFN-γ, interferon-γ; IL, interleukin; MDR1, multidrug resistance protein 1; Mr, relative molecular mass; NK-κB, nuclear factor κB; OATP2, organic anion transporting polypeptide 2; P450, cytochrome P450; PXR, pregnane X receptor; SCONT, serum from control rabbits; SHYPO, serum from rabbits with hypoxia.

    • Received October 25, 2006.
    • Accepted February 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (5)
Drug Metabolism and Disposition
Vol. 35, Issue 5
1 May 2007
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Research ArticleArticle

Animal Models of Acute Moderate Hypoxia Are Associated with a Down-Regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and Up-Regulation of CYP3A6 and P-glycoprotein in Liver

Caroline Fradette, Joëlle Batonga, Shirley Teng, Micheline Piquette-Miller and Patrick du Souich
Drug Metabolism and Disposition May 1, 2007, 35 (5) 765-771; DOI: https://doi.org/10.1124/dmd.106.013508

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Research ArticleArticle

Animal Models of Acute Moderate Hypoxia Are Associated with a Down-Regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and Up-Regulation of CYP3A6 and P-glycoprotein in Liver

Caroline Fradette, Joëlle Batonga, Shirley Teng, Micheline Piquette-Miller and Patrick du Souich
Drug Metabolism and Disposition May 1, 2007, 35 (5) 765-771; DOI: https://doi.org/10.1124/dmd.106.013508
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