The Role of Pregnane X Receptor in 2-Acetylaminofluorene-Mediated Induction of Drug Transport and -Metabolizing Enzymes in Mice

Anapolsky, Alexander; Teng, Shirley; Dixit, Santosh G; Piquette-Miller, Micheline

doi:10.1124/dmd.105.006197

Cited by 45 publications

(38 citation statements)

References 40 publications

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“…These results confirm in vitro results showing that hypoxia reduces the sensitivity of EMT6/Ro cells to doxorubicin (Adriamycin), 5-fluorouracil, and actinomycin D because of an amplification of the P-glycoprotein gene family (Sakata et al, 1991). Induction of P-glycoprotein as well as BCRP and the organic anion-transporting polypeptide 2 (OATP2) frequently occurs through activation of PXR (Anapolsky et al, 2006); however, this mechanism did not appear to play an important role in hypoxic animals because mRNA levels of BCRP and OATP2 as well as PXR were not affected. Alternatively it is plausible that binding sites for HIF-1, found on the promoter region of MDR1 (Krishnamurthy et al, 2004), may be involved in the observed hypoxia-mediated induction of P-glycoprotein.…”

supporting

confidence: 77%

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

Fradette¹,

Batonga²,

Teng³

et al. 2007

Drug Metab Dispos

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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 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 ...

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supporting

confidence: 77%

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

Fradette¹,

Batonga²,

Teng³

et al. 2007

Drug Metab Dispos

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“…The impact of PXR activation on the regulation of transporters in placenta was further assessed in pregnant wild-type and knockout mice. Activation of PXR has been shown to significantly induce the hepatic expression of Cyp3a11, Oatp2, and several of the ABC drug transporters including Mdr1, Mrp2, and Mrp3 in nonpregnant mice (Teng and Piquette-Miller, 2005;Anapolsky et al, 2006). Likewise, PCN-mediated induction of several PXR gene targets has been reported in the intestine and blood-brain barrier (Bauer et al, 2004;Cheng and Klaassen, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, largely due to increasing hormonal levels, the hepatic expression of PXR increases by approximately 20-fold during the perinatal period in mice (Masuyama et al, 2001). PXR-mediated induction of Cyp3a and several key ABC drug efflux transporters in liver such as Mdr1, Mrp2, Mrp3, and Bcrp has been demonstrated (Guo et al, 2002;Kliewer et al, 2002;Teng et al, 2003;Anapolsky et al, 2006). Likewise, PXR activation has been found to induce expression and activity of P-gp at the blood-brain barrier (Bauer et al, 2004(Bauer et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir

Piquette-Miller²

2010

Drug Metab Dispos

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ABSTRACT:The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was

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“…It has been found that this sequence also interacts with PXR and the constitutive androstane receptor. Indeed, most of the PXR ligands such as rifampicin and hyperforin have been shown to upregulate MRP2 expression in humans, mice, and rats (Fromm et al 2000, Kast et al 2002, Anapolsky et al 2006. Excess glucocorticoid concentrations increase the MRP2 mRNA levels, which implicates glucocorticoidinducible PXR activation (Kliewer et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…2A), which suggests that the induction of MRP2 in the TAM-resistant breast cancer cells is mediated through the transcriptional activation of the MRP2 gene. Since PXR is believed to be an essential transcription factor for the induction of MRP2 (Teng & Piquette-Miller 2005), and the roles of PXR in the inducible expression of MRP2 have been examined extensively (Kast et al 2002, Anapolsky et al 2006, this study compared the reporter activities in both MCF-7 and TAMR-MCF-7 cells using the PXR reporter plasmid (three copies of the PXR-responsive elements from CYP3A23 gene; Kast et al 2002). The reporter activity was significantly higher in the TAMR-MCF-7 cells than in the control MCF-7 cells (Fig.…”

Section: Involvement Of Pxr In the Enhanced Mrp2 Expression In Tam-rementioning

confidence: 99%

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells

Choi¹,

Yang²,

Roh³

et al. 2007

Endocr Relat Cancer

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Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy-responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistanceassociated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein b was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (PI3-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of PI3-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.

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The Role of Pregnane X Receptor in 2-Acetylaminofluorene-Mediated Induction of Drug Transport and -Metabolizing Enzymes in Mice

Cited by 45 publications

References 40 publications

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

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

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells

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