Pregnane X Receptor Is a Target of Farnesoid X Receptor

Jung, Diana; Mangelsdorf, David J.; Meyer, Urs

doi:10.1074/jbc.m600116200

Cited by 122 publications

(84 citation statements)

References 59 publications

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“…To our knowledge, there is no study reporting whether the gene for ABCG2, the major effl ux transporter of rosuvastatin, is a target of FXR, but indirect evidence suggests that hepatic ABCG2 expression is regulated by some nuclear receptors, such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) ( 31 ), and the latter is a target of FXR ( 32 ). Therefore, it is possible that the reduced FXR activity due to the -1G>T mutation may reduce the ABCG2 expression via effects on PXR.…”

Section: Discussionmentioning

confidence: 99%

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

Lui

Tam

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org that FXR activation is benefi cial in situations of energy excess, such as obesity and diabetes, and FXR agonists are being evaluated in preclinical studies for treating diabetes and metabolic disorders ( 2, 3 ). Although FXR functions as a bile acid receptor, studies have identifi ed that FXR also regulates multiple drug metabolizing enzyme or drug transporter genes by binding to FXR response elements and promoting transcription of target genes, suggesting that FXR may play an important role in determining the pharmacokinetics and pharmacodynamics of numerous drugs ( 4 ).Recent pharmacogenetic studies have demonstrated that drug transporters, in particular the solute carrier organic anion transporter family, member 1B1 (SLCO1B1) and ATP-binding cassette, subfamily G, member 2 (ABCG2), play an important role in determining the pharmacokinetics and pharmacodynamics of statins ( 5-7 ). It is known that the tissue protein expression of drug transporters is highly variable between individuals and that these interindividual variations in transporter expression may result in variabilities in lipid response to statins ( 4 ). Loss of function single nucleotide polymorphisms (SNP) in the coding region of the SLCO1B1 and ABCG2 genes were associated with altered statin exposure and lipid-lowering effects ( 5-7 ), but these SNPs did not appear to affect overall protein expression ( 4,8 ). Instead, the decreased transport activity of SLCO1B1 and ABCG2 associated with these SNPs is thought to result from membrane-traffi cking defects ( 4, 9, 10 ).FXR regulates several drug transporters involved in statin disposition, including SLCO1B1, SLCO1B3, sodiumtaurocholate cotransporting polypeptide (NTCP), and The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which is activated by bile acids. Activation of FXR leads to altered expression of many genes responsible for bile acid and lipid and glucose metabolism and transport, resulting in decreased intracellular bile acid concentrations and reduced plasma glucose and triglyceride levels ( 1, 2 ). Current evidence suggests

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Section: Discussionmentioning

confidence: 99%

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

Lui

Tam

et al. 2012

Journal of Lipid Research

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“…BAs are well-known activators for both FXR and PXR (Xie et al, 2001;Gnerre et al, 2004, Staudinger et al, 2001Hylemon et al, 2009). FXR can also up-regulate PXR expression (Jung et al, 2006). Thus, an increase in BA can activate FXR and PXR in the SI (and in liver), ultimately stimulating the expression of CYP3A and other P450s that TABLE 1 Dietary effects on pharmacokinetic parameters for orally administered MDZ in WT and IE-Cpr-null mice WT and IE-Cpr-null mice (2-to 4-month-old male) from the regular diet or synthetic diet groups were given a single oral dose of MDZ (30 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

“…BAs are also signaling molecules, which regulate gene expression through nuclear receptors, including farnesoid-X-receptor (FXR) and pregnane-X-receptor (PXR) (Makishima et al, 1999;Parks et al, 1999;Wang et al, 1999;Xie et al, 2001). PXR, which regulates the expression of several P450s, can be activated by FXR (Jung et al, 2006); the latter plays a key role in the regulation of BA homeostasis (Goodwin et al, 2000;Kim et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

et al. 2012

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The study was originally designed to test the hypothesis that the compensatory increase in intestinal P450 (cytochrome P450) expression in the intestinal epithelium-specific P450 reductase (CPR) knockout (IE-Cpr-null) mice was attributable to decreased metabolism of putative P450 inducers present in the diet. Thus, we determined the impact of a dietary change from regular rodent chow to a synthetic diet devoid of phytochemicals on the expression of P450 enzymes in the small intestine (SI) and liver of wild-type (WT) and IE-Cpr-null mice. The dietary change diminished expression of CYP1A, 2B, 2C, and 3A in SI and CYP2B, 2C, and 3A in liver of both WT and IE-Cpr-null mice. However, the compensatory increase in SI P450 expression still occurred in IE-Cpr-null, compared with WT, mice, on the synthetic diet. The diet change-induced decrease in P450 expression was accompanied by decreases in microsomal midazolam-hydroxylase activity in vitro and first-pass clearance of midazolam in vivo in WT mice. Further studies showed that the dietary change, but not Cpr deletion, caused large decreases in bile acid (BA) levels in plasma, liver, SI, and intestinal content and that treatment of WT mice on the synthetic diet with GW4064, a farnesoid-X-receptor agonist, restored the levels of CYP3A expression in both liver and SI to those seen in mice fed with regular chow. Taken together, these results highlight the vital role of diet in maintaining adequate expression of major drug-metabolizing P450s and their associated drug-metabolizing activities in the digestive tract and suggest potential involvement of BA signaling in the regulatory mechanisms.

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“…2001), recent findings indicate that primary bile acids can also induce CYP3A as a consequence of farnesoid X receptor activation, both directly through the transactivation of CYP3A4 as an farnesoid X receptor target gene (Gnerre et al, 2004) and indirectly through the transcriptional up-regulation of PXR (Jung et al, 2006). Certain secondary bile acids, such as lithocholic acid and ursodeoxycholic acid, are known to activate murine and human PXR, consistent with a conserved role for PXR in protection from cholestasis (Uppal et al, 2007).…”

Section: Downloaded Frommentioning

confidence: 99%

Human Pregnane X Receptor Activation and CYP3A4/CYP2B6 Induction by 2,3-Oxidosqualene:Lanosterol Cyclase Inhibition

Duniec-Dmuchowski¹,

Fang²,

Strom³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The effects of [4-(6-allyl-methyl-amino-hexyloxy)-2-fluoro-phenyl]-(4-bromophenyl)-methanone fumarate (Ro 48-8071), an inhibitor of 2,3-oxidosqualene:lanosterol cyclase (cyclase), were evaluated on CYP3A4 and CYP2B6 mRNA content in primary cultured human hepatocytes. In seven hepatocyte culture preparations, 24-h treatment with 3, 10, or 30 M Ro 48-8071 produced median increases in CYP3A4 mRNA content that were 2.2-, 7.1-, and 8.5-fold greater than untreated control, respectively, and produced increases in CYP2B6 mRNA content that were 3.0-, 4.6-, and 3.4-fold greater than control, respectively. Increases in CYP3A4 immunoreactive protein content were also measured in Ro 48-8071-treated hepatocytes. To evaluate the effects of cyclase inhibitor treatments further, a pregnane X receptor ( A primary mode of defense that is used by animals against their chemical environments involves recognition by a "xenobiotic-sensing" receptor followed by the induction of phase I and phase II xenobiotic-metabolizing enzymes, as well as "phase III" transporters. As the archetype of this mechanism, many xenobiotics bind to the pregnane X receptor (PXR), owing to the receptor's unusually accommodating ligand-binding pocket (Watkins et al., , 2003. On ligand binding, PXR, in partnership with the retinoic X receptor, is transformed into an active transcription factor that increases the expression of target genes, which include members of the CYP3A family (e.g., CYP3A23 in rat, CYP3A11 in mouse, and CYP3A4 in human). These CYP3A enzymes catalyze the phase I metabolism of numerous xenobiotic substrates, including a large number of clinically used drugs (Quattrochi and Guzelian, 2001).In addition to serving as a xenobiotic recognition and metabolizing system, PXR and CYP3A enzymes are increasingly perceived to function in the metabolism of endogenous molecules. For example, the cholestatic secondary bile acid, lithocholate, both activates PXR and is a substrate for CYP3A (Staudinger et al., 2001;Xie et al., 2001). We have used chemical inhibitors of various steps of the cholesterol biosynthetic pathway as an approach for identifying endogenous modulators of hepatic cytochrome P450 expression (Fig. 1). In this regard, we have reported that inhibitors of squalene synthase (e.g., squalestatin 1), the first committed step in cholesterol biosynthesis, selectively induce CYP2B expression in primary cultured rat hepatocytes and rat liver through a mechanism that requires the

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Pregnane X Receptor Is a Target of Farnesoid X Receptor

Cited by 122 publications

References 59 publications

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin

Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

Human Pregnane X Receptor Activation and CYP3A4/CYP2B6 Induction by 2,3-Oxidosqualene:Lanosterol Cyclase Inhibition

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