Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Pávek, Petr; Pospěchová, Kateřina; Svecova, Lucie; Syrová, Zdeňka; Stejskalová, Lucie; Blažková, Jana; Dvořák, Zdeněk; Blahoš, Jaroslav

doi:10.1016/j.bcp.2009.08.017

Cited by 61 publications

(56 citation statements)

References 38 publications

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“…However, Cyp27a1-null mice showed a normal phenotype in the vitamin D activation pathway (15). Over the years, the identification of the nuclear hormone response elements in the Cyp3a4 gene promoter has drawn attention to the most abundant P450 in human liver and intestine as a possible vitamin D 25-hydroxylase (46)(47)(48)(49)(50), although the vitamin D receptor is undetectable in the liver (51). CYP3A4 is a well-known xenobiotic-metabolizing enzyme and can act on approximately half of the drugs in use.…”

Section: Discussionmentioning

confidence: 99%

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

Zhu

Ochalek

Kaufmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

273

140

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Bioactivation of vitamin D consists of two sequential hydroxylation steps to produce 1α, 25-dihydroxyvitamin D 3 . It is clear that the second or 1α-hydroxylation step is carried out by a single enzyme, 25-hydroxyvitamin D 1α-hydroxylase CYP27B1. However, it is not certain what enzyme or enzymes are responsible for the initial 25-hydroxylation. An excellent case has been made for vitamin D 25-hydroxylase CYP2R1, but this hypothesis has not yet been tested. We have now produced Cyp2r1 −/− mice. These mice had greater than 50% reduction in serum 25-hydroxyvitamin D 3 . Curiously, the 1α,25-dihydroxyvitamin D 3 level in the serum remained unchanged. These mice presented no health issues. A double knockout of Cyp2r1 and Cyp27a1 maintained a similar circulating level of 25-hydroxyvitamin D 3 and 1α,25-dihydroxyvitamin D 3 . Our results support the idea that the CYP2R1 is the major enzyme responsible for 25-hydroxylation of vitamin D, but clearly a second, as-yet unknown, enzyme is another contributor to this important step in vitamin D activation. 25-Hydroxyvitamin D 1a-hydroxylase CYP27B1 (CYP27B1) has long been identified as the sole 25(OH)D 3 1α-hydroxylase in a number of species, including human (5), whereas the specific vitamin D 3 25-hydroxylase has yet to be elucidated. Many candidates have been proposed, but in vivo proof has yet to appear. Most of the potential 25-hydroxylases are primarily expressed in the liver, and all are members of the cytochrome P450 family (CYP2C11, CYP2D25, CYP27A1, CYP3A4, CYP2R1, and CYP2J2/3) (4). Among them, CYP27A1 and CYP2R1 are considered the most promising candidates for vitamin D 25-hydroxylation. CYP27A1, also known as the sterol 27-hydroxylase, is a key enzyme in bile acid formation (6, 7). Recombinant CYP27A1 is able to catalyze multiple oxidation reactions with broad substrate specificity in vitro (8)(9)(10)(11)(12)(13)(14). However, it is a lowaffinity, high-capacity vitamin D 25-hydroxylase and is certainly involved in steroidogenesis. Ablation of Cyp27a1 in mouse disrupted cholesterol metabolism and bile acid synthesis severely but did not alter vitamin D metabolism (15, 16). Indeed, these animals had supranormal serum 25(OH)D 3 levels (15). Patients with cerebrotendinous xanthomatosis caused by mutations in the Cyp27a1 gene show dysfunctions that result from reduced bile acid production, but generally do not present vitamin D-related pathology (17, 18). These findings suggest that CYP27A1 is a minor factor, if it plays a role at all, in 25(OH)D 3 synthesis in vivo. CYP2R1 was recently identified as vitamin D 25-hydroxylase in mouse and human through the screening of a liver cDNA library from Cyp27a1-null mice (19). Heterologous expression of CYP2R1 in HEK cells, yeast, and Escherichia coli revealed that CYP2R1 catalyzes 25-hydroxylation of both vitamin D 3 and vitamin D 2 at similar rate, and much more efficiently than CYP27A1 (19-21). The clinical relevance of CYP2R1 as vitamin D 25-hydroxylase is from a handful of patients of Nigerian and Saudi Arabian decent havi...

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Section: Discussionmentioning

confidence: 99%

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

Zhu

Ochalek

Kaufmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

273

140

View full text Add to dashboard Cite

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“…However, hVDR has been thought of as a highaffinity nuclear receptor with a different agonist/inhibitor selection mechanism from that of hPXR (Schmiedlin-Ren et al, 2001). Moreover, ligand-induced hVDR transactivation of CYP3A4 in its classical target tissue, the intestine, differs from hPXR-mediated CYP3A4 regulation in hepatocytes (Schmiedlin-Ren et al, 2001;Pavek et al, 2010). Studies are ongoing in our laboratory to clarify the differential regulation mechanisms of different nuclear receptors.…”

Section: Discussionmentioning

confidence: 99%

Camptothecin Attenuates Cytochrome P450 3A4 Induction by Blocking the Activation of Human Pregnane X Receptor

Chen¹,

Tang²,

Robbins³

et al. 2010

J Pharmacol Exp Ther

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Differential regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in cancer therapy. Due to the extremely important role of cytochrome P450 3A4 (CYP3A4) in drug metabolism and the dominant regulation of human pregnane X receptor (hPXR) on CYP3A4, finding inhibitors for hPXR could provide a unique tool to control drug efficacies in cancer therapy. Camptothecin (CPT) was demonstrated as a novel and potent inhibitor (IC 50 ϭ 0.58 M) of an hPXR-mediated transcriptional regulation on CYP3A4 in this study. In contrast, one of its analogs, irinotecan (CPT-11), was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 but had effects on neither the competition of ligand binding nor the formation of the hPXR and retinoid X receptor ␣ heterodimer, nor the interaction between the regulatory complex and DNA-responsive elements. CPT treatment resulted in delayed metabolism of nifedipine in human hepatocytes treated with rifampicin, suggesting a potential prevention of drug-drug interactions between CYP3A4 inducers and CYP3A4-metabolized drugs. Because CPT is the leading compound of topoisomerase I inhibitors, which comprise a quickly developing class of anticancer agents, the findings indicate the potential of a new class of compounds to modify hPXR activity as agonists/inhibitors and are important in the development of CPT analogs.Topoisomerase I inhibitors are a quickly developing class of anticancer agents. Clinical trials with the leading compound of this class of drugs, camptothecin (CPT), showed remarkable anticancer activity by interrupting DNA replication in cancer cells (Chen and Liu, 1994). Several semisynthetic derivatives of CPT, such as topotecan and irinotecan (CPT-11), have been used in cancer chemotherapy (Creemers et al., 1994). Although the main mechanism by which topoisomerase I inhibitors produce their antitumor effects has been widely investigated, both the mechanism of interindividual variability in the plasma disposition and the potential to regulate the efficacy of other compounds when used in combination are not fully understood (van Warmerdam et al., 1996).Up-regulation/down-regulation of drug-metabolizing enzymes (DMEs) is a common cause of unpredictable drug effects during cancer therapy (Rochat, 2005), especially the alteration in the expression of cytochrome P450 3A4 (CYP3A4), an enzyme involved in the metabolism of 60% of drugs (Guengerich, 1999), including many anticancer drugs. Hu- ABBREVIATIONS: CPT, camptothecin; DME, drug-metabolizing enzyme; hPXR, human pregnane X receptor; DDI, drug-drug interaction; SRC-1, steroid receptor cofactor-1; 1,25-(OH) 2 VD 3 , 1␣, 25-dihydroxyvitamin D3; CITCO,

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“…In the small intestine, CYP3A4 is a major drug-metabolizing enzyme, and its expression was induced by 1a,25-dihydroxyvitamin D 3 through the vitamin D receptor Pavek et al, 2010). We evaluated CYP3A4 expression, activity, and inducibility.…”

Section: Downloaded Frommentioning

confidence: 99%

Generation of Enterocyte-Like Cells with Pharmacokinetic Functions from Human Induced Pluripotent Stem Cells Using Small-Molecule Compounds

et al. 2015

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The small intestine plays an important role in all aspects of pharmacokinetics, but there is no system for the comprehensive evaluation of small-intestinal pharmacokinetics, including drug metabolism and absorption. In this study, we aimed to construct an intestinal pharmacokinetics evaluation system and to generate pharmacokinetically functional enterocytes from human induced pluripotent stem cells. Using activin A and fibroblast growth factor 2, we differentiated these stem cells into intestinal stem cell-like cells, and the resulting cells were differentiated into enterocytes in a medium containing epidermal growth factor and small-molecule compounds. The differentiated cells expressed intestinal marker genes and drug transporters. The expression of sucrase-isomaltase, an intestine-specific marker, was markedly increased by small-molecule compounds. The cells exhibited activities of drug-metabolizing enzymes expressed in enterocytes, including CYP1A1/2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT, and sulfotransferase. Fluorescence-labeled dipeptide uptake into the cells was observed and was inhibited by ibuprofen, an inhibitor of the intestinal oligopeptide transporter solute carrier 15A1/PEPT1. CYP3A4 mRNA expression level was increased by these compounds and induced by the addition of 1a,25-dihydroxyvitamin D 3 . CYP3A4/5 activity was also induced by 1a,25-dihydroxyvitamin D 3 in cells differentiated in the presence of the compounds. All these results show that we have generated enterocyte-like cells that have pharmacokinetic functions, and we have identified small-molecule compounds that are effective for promoting intestinal differentiation and the gain of pharmacokinetic functions. Our enterocyte-like cells would be useful material for developing a novel evaluation system to predict human intestinal pharmacokinetics.

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Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Cited by 61 publications

References 38 publications

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

Camptothecin Attenuates Cytochrome P450 3A4 Induction by Blocking the Activation of Human Pregnane X Receptor

Generation of Enterocyte-Like Cells with Pharmacokinetic Functions from Human Induced Pluripotent Stem Cells Using Small-Molecule Compounds

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