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

Abstract

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 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 downregulation of P450 isoforms were interferon-␥, interleukin-1␤ (IL-1␤), 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.In patients with cardiorespiratory diseases, acute hypoxemia appears to reduce the ability of cytochrome P450 isoforms to catalyze the biotransformation of xenobiotics. Patients with pulmonary insufficiency who show an impairment of their general state present an increased incidence of adverse effects, e.g., grand mal seizures, associated with the administration of "usual" doses of theophylline. Theophylline clearance is significantly reduced in patients with acute cardiogenic pulmonary edema (Piafsky et al., 1977) and in patients with worsening airway obstruction, severe bronchial obstruction, congestive heart failure, and pneumonia (Vozeh et al., 1978).In humans, at therapeutic concentrations, the biotransformation of theophylline is primarily catalyzed by CYP1A2, whereas CYP2D6, 2E1, and 3A4 exhibit low affinity and variable capacity (Ha et al., 1995). Rabbits exposed to a fractional concentration of inspired O 2 (FiO 2 ) of 10% for 24 h demonstrate a reduced clearance of theophylline and decreased expression of CYP1A1 and 1A2, although the expression of CYP3A6 is increased (Kurdi et al., 1999). In rabbits subjected to acute moderate hypoxia, hepatic down-regulation of CYP1A1 and 1A2 is triggered by serum mediators, e.g., interferon-␥ (IFN-␥), interleukin 2 (IL-2), and IL-1␤; the up-regulation of CYP3A6 is, at least in part, associated with erythropoietin (Epo) (Fradette et ...

Effects of elevated dissolved carbon dioxide and perfluorooctane sulfonic acid, given singly and in combination, on steroidogenic and biotransformation pathways of Atlantic cod

“…Elsewhere, hypoxia was also shown to decrease CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity in zebrafish embryos (Fleming and Di Giulio, 2011) and cyp1a mRNA levels in Atlantic cod liver (Olsvik et al, 2006). Mammalian in vivo studies using rabbit, and rodent in vitro hepatocyte studies also showed decreases in cyp1a and cyp1a2 mRNA and protein expression by hypoxia, whose effects on CYP1As are mediated through HIF-1α, cellular cytokines and reactive oxygen species (ROS) (Fradette et al, 2007;Fradette and Du Souich, 2004). These studies are direct opposite of the effects of hypercapnia observed in the present study showing persistent increase of cyp1a mRNA in all sampling days.…”

Endocrine, biotransformation, and oxidative stress responses in salmon hepatocytes exposed to chemically induced hypoxia and perfluorooctane sulfonamide (PFOSA), given singly or in combination

“…Elsewhere, exposure to hypoxia (dissolved oxygen, DO: 1.7 mg/L for 2 to 4 weeks) produced significant decreases in hepatic cyp1a mRNA and protein levels (du Souich and Fradette 2011;Rahman and Thomas 2012). Some studies have suggested post-transcriptional inhibition of CYP1A activity (Fradette et al 2007). It should be acknowledged that gene expression analysis may not directly be translated into enzyme activity.…”

“…Cells adapt to reduction in oxygen levels by shifting energy production from mitochondrial fatty acid β-oxidation to glycolysis during periods of cellular hypoxia (Liu et al 2014). Elsewhere, in vivo mammalian studies using rabbit, and rodent in vitro hepatocyte studies reported decreases in cyp1a and cyp1a2 mRNA and protein expression by hypoxia, whose effects are mediated through HIF-1α, cellular cytokines and ROS (Fradette et al 2007;Fradette and du Souich 2004). While these studies may show some discrepancies with our findings, there are direct relevance of the effects of hypoxia observed in the present study showing persistent increase of cyp1a, cyp3a and pxr mRNA.…”

Regulation of EC-SOD in Hypoxic Adipocytes

“…In these hypoxic conditions, it has been recognized that accumulated HIF-1α increases a wide variety of genes including vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), erythropoietin (EPO) and cytochrome p450 (CYP) 3A6 to ensure adaptation to low-oxygen tension (Levy et al, 1995;Lee et al, 1997). On the other hand, the expression of CYP1A2, 2B and 2C are decreased by the activation of HIF-1α (Olsvik et al, 2006;Fradette et al, 2007). Further, it has been reported that both hypoxia and hypoxia mimetics increase ROS generation and dysregulate adipocytokines, and these conditions lead to and/or promote metabolic disorders (Schuster et al, 1989;Hosogai et al, 2007).…”