Induction of Rat Organic Anion Transporting Polypeptide 2 by Pregnenolone-16α-carbonitrile Is via Interaction with Pregnane X Receptor

Guo, Grace L.; Staudinger, Jeff; Ogura, K.; Klaassen, Curtis D.

doi:10.1124/mol.61.4.832

Cited by 119 publications

(71 citation statements)

References 32 publications

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“…In addition to up-regulation of some transporters, PCN administration also decreased Cnt2 mRNA in jejunum and ileum of WT mice, but not in PXR-null mice, indicating that the decrease is mediated via PXR. Regulation of rat and mouse hepatic Oatp1a4 (Staudinger et al, 2001a;Guo et al, 2002c) and Mrp3 (Teng et al, 2003), as well as mouse intestinal Mdr1a (Geick et al, 2001;Matheny et al, 2004) by PCN, has been reported previously. The present study confirms that mouse hepatic Oatp1a4 and Mrp3, and intestinal Mdr1a regulation by PCN is PXR-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the limited availability of good antibodies and specific substrates for each transporter, regulation of transporters has mainly been determined at the mRNA level. However, the increase in expression of Oatp1a4 mRNA correlates with a marked increase in clearance of ouabain by the liver (Klaassen, 1974b;Eaton and Klaassen, 1978;Guo et al, 2002c).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

Cheng¹,

Klaassen²

2006

Drug Metab Dispos

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ABSTRACT:Multiple transporter systems are involved in the disposition of xenobiotics and endogenous compounds. The pregnane X receptor (PXR) is a major chemical sensor known to activate the expression of CYP3A/Cyp3a in humans and rodents. The purpose of this study is to systematically determine whether the major xenobiotic transporters in liver, kidney, duodenum, jejunum, and ileum are induced by pregnenolone-16␣-carbonitrile (PCN), and whether this increase is mediated by the nuclear receptor PXR. In liver, PCN induced the expression of Oatp1a4 and Mrp3 mRNA in wild-type (WT) mouse liver, but not in PXR-null mice. In kidney, PCN did not alter the expression of any drug transporter. In duodenum, PCN increased Abca1 and Mdr1a mRNA expression in WT mice, but not in PXR-null mice. In jejunum and ileum, PCN increased Mdr1a and Mrp2 mRNA, but decreased Cnt2 mRNA in WT mice, but none of these transporters was altered when PCN was administered to PXR-null mice. Therefore, PCN regulates the expression of some transporters, namely, Oatp1a4 and Mrp3 in liver, as well as Abca1, Cnt2, Mdr1a, and Mrp2 in small intestine via a PXR-mediated mechanism.The pregnane X receptor (PXR, NR1I2), also called steroid-xenobiotic receptor or pregnane-activated receptor, is an orphan nuclear receptor first identified by Kliewer and coworkers (Lehmann et al., 1998). PXRs have been characterized in rats, mice, humans, rabbits, and chickens. Mouse PXR shares 95% sequence similarity to rat and 77% to human PXR (Zhang et al., 1999;Moore et al., 2003).PXR is a master regulator of phase I and II metabolism of xenobiotics. Upon ligand binding, PXR forms a heterodimer with the retinoid X receptor ␣ and then transactivates target genes. PXR ligands generally induce Cyp3a/CYP3A genes in rats, mice, and humans (Goodwin et al., 2002;Guo et al., 2002b;Cheng et al., 2005b). One exception is CYP3A41, which is down-regulated by dexamethasone (DEX) in a PXR-dependent manner (Anakk et al., 2004). Pregnenolone-16␣-carbonitrile (PCN) also regulates phase II drug-metabolizing enzymes, such as glutathione S-transferase ␣1 and 1, rat UDP-glucuronosyltransferase 1a1 (Ugt1a1) (Chen et al., 2003), and sulfotransferase 1b1 (Dunn et al., 1999). In addition, PCN induces the expression of some transprters, such as rat Abca1 (Sporstol et al., 2005), human MRP2, and MRP3 (Kretschmer and Baldwin, 2005).The regulation of hepatic and small intestinal gene expression by two potent rat PXR agonists, L-742694 and DEX, has been examined after oral administration to female Sprague-Dawley rats using DNA microarray analysis (Hartley et al., 2004). Both L-742694 and DEX elicited robust increases in gene expression of Cyp3a1/23, Cyp3a18, Ugt1a1, Ugt2b1, and Oatp1a4 in rat liver. However, both L-742694 and DEX suppressed rat Cyp3a1/23, Cyp3a18, Ugt1a1, Ugt2b1, Oatp1a4, and Mrp3 expression in intestine (Hartley et al., 2004). There was a distinct lack of coordinated interorgan expression of genes common to both hepatic and intestinal tissues in rats (Hartley et al., 2004).Mice and rats...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

Cheng¹,

Klaassen²

2006

Drug Metab Dispos

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“…39 Subsequent studies have shown that potentially cholestatic bile salts, including deoxycholate, may also activate PXR. 12,40 PXR in turn induces proteins of phase I metabolism (e.g., CYP3A) and hepatic transporters 11,41 (Mdr P-glycoprotein, Oatp2), resulting in the detoxification and elimination of toxic bile salts and xenobiotic substances. In the present study, we show that Oatp2 expression was increased after CA feeding in the rat, which is in contrast to the observed down-regulation of Ntcp, Oatp1, and Oatp4.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Rat Organic Anion Transporters in Bile Salt–Induced Cholestatic Hepatitis: Effect of Ursodeoxycholate

et al. 2003

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Hepatic uptake of organic anions, including bile salts, is mediated by members of the organic anion-transporting polypeptide (Oatp) family. In rat liver, Oatp1 (Slc21a1), Oatp2 (Slc21a5), and Oatp4 (Slca10) are expressed at the basolateral membrane of hepatocytes and may be differentially regulated under pathophysiologic conditions such as cholestasis. The aim of this study was to determine the effects of cholic acid (CA) and ursodeoxycholic acid (UDCA) on the expression of Oatp4 compared with Ntcp, Oatp1, and Oatp2. Wistar rats were fed with CA (0.5%) or both CA (0.5%) and UDCA (0.25%) for 3 weeks. Oatp expression was studied by Northern and Western blot analysis as well as immunofluorescence analysis. Transport function was compared measuring biliary secretion of 14 C-CA and 14 Ctaurocholic acid (TCA). In CA-fed animals, biliary secretion of 14 C-CA and 14 C-TCA was markedly delayed over 40 minutes compared with controls. Accordingly, Oatp4 protein was significantly down-regulated in CA-fed animals together with Oatp1 and Ntcp. Cofeeding of CA plus UDCA prevented the impairment of 14 C-CA and 14 C-TCA secretion and the downregulation of Oatp4. Oatp4 messenger RNA (mRNA) levels did not differ significantly between bile salt-fed groups, suggesting a posttranscriptional effect of CA on Oatp4 expression. In contrast to Oatp1 and Oatp4, Oatp2 protein expression was increased by CA feeding, indicating a differential regulation of Oatp transporters. In conclusion, we show that CA feeding may cause cholestasis associated with a posttranscriptional down-regulation of Oatp4. UDCA may prevent impairment of hepatic function by restoring hepatic transporter expression. (HEPATOLOGY 2003;38:187-195.)

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“…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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Induction of Rat Organic Anion Transporting Polypeptide 2 by Pregnenolone-16α-carbonitrile Is via Interaction with Pregnane X Receptor

Cited by 119 publications

References 32 publications

Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

Regulation of Rat Organic Anion Transporters in Bile Salt–Induced Cholestatic Hepatitis: Effect of Ursodeoxycholate

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

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