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

• Published in: Drug metabolism and disposition Vol. 35; no. 5; pp. 765 - 771
• Main Authors: FRADETTE, Caroline, BATONGA, Joëlle, TENG, Shirley, PIQUETTE-MILLER, Micheline, DU SOUICH, Patrick
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.05.2007
• Subjects: Acute Disease; Animals; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological and medical sciences; Cell Hypoxia; Cells, Cultured; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP3A; Down-Regulation - drug effects; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hypoxia - physiopathology; Immunoblotting; Isoenzymes - genetics; Isoenzymes - metabolism; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Medical sciences; Models, Animal; Oxygen - metabolism; Oxygen - pharmacology; Oxygen Consumption; Pharmacology. Drug treatments; Pregnane X Receptor; Rabbits; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Up-Regulation - drug effects; Animal model; Oxygen; Digestive system; Enzyme; Isozyme; Acute; Cytochrome P450; Liver; P Glycoprotein; Immunoglobulin receptor; 2B4 receptor; Environmental factor; Hypoxia
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.106.013508

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 O 2 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.