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Drug Metabolism and Disposition Fast Forward
First published on February 15, 2007; DOI: 10.1124/dmd.106.013508

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Received for publication October 26, 2006.
Revised February 8, 2007.
Accepted for publication February 12, 2007.

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 1, Joelle Batonga 1, Shirley Teng 2, Micheline Piquette-Miller 2, Patrick du Souich 1*

1 University of Montreal 2 University of Toronto

* Address correspondence to: E-mail: patrick.du.souich{at}umontreal.ca

Abstract

In vivo, 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, since 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 mmHg. Compared with rabbits breathing room air, hypoxia 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 neutralisation experiments. The serum mediators responsible for the down-regulation of P450 isoforms were interferon-{gamma}, interleukin-1{beta} (IL-1{beta}) 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 upregulated in the livers of hypoxic rats.


Key words: CYP expression, CYP1A, CYP2B, CYP2C, CYP3A, interleukins, ischemic/hypoxic injury, organic anion transport, p-glycoprotein, PXR


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Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model
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