Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hydroxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1alpha-hydroxylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1alpha,25-dihydroxyvitamin D(3). A five-step inactivation pathway from 1alpha,25-(OH)(2)D(3) to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally induced in vitamin D target cells by the action of 1alpha,25-(OH)(2)D(3). On the basis of alignments and crystal structures of other CYPs, homology models of vitamin-D-related CYPs have been generated. Two human forms of rickets caused by mutations of CYP2R1 and CYP27B1, as well as mouse knockout models of CYP27A1, CYP27B1 and CYP24A1, are helping us to establish the full in vivo physiological roles of the vitamin-D-related hydroxylases.
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PMID:Enzymes involved in the activation and inactivation of vitamin D. 1554 53

The vitamin D receptor (VDR) mediates the effects of 1,25(OH)(2)D(3), the active form of vitamin D. The human VDRB1 isoform differs from the originally described VDR by an N-terminal extension of 50 amino acids. Here we investigate cell-, promoter-, and ligand-specific transactivation by the VDRB1 isoform. Transactivation by these isoforms of the cytochrome P450 CYP24 promoter was compared in kidney (HEK293 and COS1), tumor-derived colon (Caco-2, LS174T, and HCT15), and mammary (HS578T and MCF7) cell lines. VDRB1 transactivation in response to 1,25(OH)(2)D(3) was greater in COS1 and HCT15 cells (145%), lower in HEK293 and Caco-2 cells (70-85%) and similar in other cell lines tested. By contrast, on the cytochrome P450 CYP3A4 promoter, 1,25(OH)(2)D(3)-induced VDRB1 transactivation was significantly lower than VDRA in Caco-2 (68%), but comparable to VDRA in HEK293 and COS1 cells. Ligand-dependence of VDRB1 differential transactivation was investigated using the secondary bile acid lithocholic acid (LCA). On the CYP24 promoter LCA-induced transactivation was similar for both isoforms in COS1, whereas in Caco-2 and HEK293 cells VDRB1 was less active. On the CYP3A4 promoter, LCA activation of VDRB1 was comparable to VDRA in all the cell lines tested. Mutational analysis indicated that both the 1,25(OH)(2)D(3) and LCA-regulated activities of both VDR isoforms required a functional ligand-dependent activation function (AF-2) domain. In gel shift assays VDR:DNA complex formation was stronger in the presence of 1,25(OH)(2)D(3) than with LCA. These results indicate that regulation of VDRB1 transactivation activity is dependent on cellular context, promoter, and the nature of the ligand.
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PMID:Promoter-, cell-, and ligand-specific transactivation responses of the VDRB1 isoform. 1599 66

The decline in bone mineral density that occurs after long-term treatment with some antiepileptic drugs is thought to be mediated by increased vitamin D(3) metabolism. In this study, we show that the inducible enzyme CYP3A4 is a major source of oxidative metabolism of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] in human liver and small intestine and could contribute to this adverse effect. Heterologously-expressed CYP3A4 catalyzed the 23- and 24-hydroxylation of 1,25(OH)(2)D(3). No human microsomal cytochrome P450 enzyme tested, other than CYP3A5, supported these reactions. CYP3A4 exhibited opposite product stereochemical preference compared with that of CYP24A1, a known 1,25(OH)(2)D(3) hydroxylase. The three major metabolites generated by CYP3A4 were 1,23R,25(OH)(3)D(3), 1,24S,25(OH)(3)D(3), and 1,23S,25(OH)(3)D(3). Although the metabolic clearance of CYP3A4 was less than that of CYP24A1, comparison of metabolite profiles and experiments using CYP3A-specific inhibitors indicated that CYP3A4 was the dominant source of 1,25(OH)(2)D(3) 23- and 24-hydroxylase activity in both human small intestine and liver. Consistent with this observation, analysis of mRNA isolated from human intestine and liver (including samples from donors treated with phenytoin) revealed a general absence of CYP24A1 mRNA. In addition, expression of CYP3A4 mRNA in a panel of duodenal samples was significantly correlated with the mRNA level of a known vitamin D receptor gene target, calbindin-D9K. These and other data suggest that induction of CYP3A4-dependent 1,25(OH)(2)D(3) metabolism by antiepileptic drugs and other PXR ligands may diminish intestinal effects of the hormone and contribute to osteomalacia.
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PMID:Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. 1620 22

The balance between bioactivation and degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is critical for ensuring appropriate biological effects of vitamin D. Cytochrome P450, family 24-mediated (CYP24-mediated) 24-hydroxylation of 1,25(OH)2D3 is an important step in the catabolism of 1,25(OH)2D3. The enzyme is directly regulated by vitamin D receptor (VDR), and it is expressed mainly in the kidney, where VDR is also abundant. A recent report suggests that activation of steroid and xenobiotic receptor (SXR) also enhances the expression of CYP24, providing a new molecular mechanism of drug-induced osteomalacia. However, here we showed that activation of SXR did not induce CYP24 expression in vitro and in vivo, nor did it transactivate the CYP24 promoter. Instead, SXR inhibited VDR-mediated CYP24 promoter activity, and CYP24 expression was very low in tissues containing high levels of SXR, including the small intestine. Moreover, 1,25(OH)2D3-induced CYP24 expression was enhanced in mice lacking the SXR ortholog pregnane X receptor, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite demonstration of marked CYP3A4 induction. Combined with our previous findings that CYP3A4, not CYP24, plays the dominant role in hydroxylation of 1,25(OH)2D3 in human liver and intestine, our results indicate that SXR has a dual role in mediating vitamin D catabolism and drug-induced osteomalacia.
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PMID:Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. 1701 48

CYP27A1, CYP27B1, and CYP24A1 are members of the cytochrome P450 superfamily, and key enzymes of vitamin D(3) metabolism. CYP27A1 produced at least seven forms of minor metabolites including 1alpha, 25 (OH) (2)D(3) in addition to the major metabolite 25 (OH) D(3). In contrast, CYP27B1 appears to be a special enzyme to catalyze the hydroxylation at C-1alpha position of 25 (OH) D(3). Mutagenesis studies of CYP27B1 revealed the amino acid residues involved in substrate binding or interaction between CYP27B1 and adreno-doxin. On CYP24A1-dependent metabolism, remarkable metabolic processes of 1alpha, 25 (OH) (2)D(3) were observed. Rat CYP24A1 catalyzed six sequential monooxygenation reactions that convert 1alpha, 25 (OH) (2)D(3) into calcitroic acid. In addition to the C-24 oxidation pathway, human CYP24A1 catalyzed also C-23 oxidation pathway to produce 1alpha, 25 (OH) (2)D(3)-26, 23-lactone. Surprisingly, more than 70% of the vitamin D metabolites observed in a living body were found to be the products formed by the activities of CYP27A1, CYP27B1, and CYP24A1. In addition to the mitochondrial P450s, microsomal P450s also play important roles in vitamin D metabolism. Recent reports suggest that human microsomal CYP2R1 is more important than CYP27A1 as a vitamin D 25-hydroxylase. The decline in bone mineral density that occurs after long-term treatment with some antiepileptic drugs appears to be due to the increased 1alpha, 25 (OH) (2)D(3) metabolism by CYP3A4. Some vitamin D analogs are good substrates for CYP3A1 while CYP24A1 is responsible for metabolism of most of vitamin D analogs.
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PMID:[Recent studies on vitamin D metabolizing enzymes]. 1681 72

Homology models of cytochrome P450 24A1 (CYP24A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using molecular operating environment (MOE) software the lowest energy CYP24A1 model was then assessed for stereochemical quality and side chain environment. Further active site optimisation of the CYP24A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP24A1 model. The natural substrate, 1,25-dihydroxyvitamin D(3) (calcitriol) and the CYP24 inhibitor (R)-N-(2-(1H-imidazol-1-yl)-2-phenylethyl)-4'-chlorobiphenyl-4-carboxamide ((R)-VID-400) were docked into the model allowing further validation of the active site architecture. Using the docking studies structurally and functionally important residues were identified with subsequent characterisation of secondary structure.
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PMID:Homology model of 1alpha,25-dihydroxyvitamin D3 24-hydroxylase cytochrome P450 24A1 (CYP24A1): active site architecture and ligand binding. 1724 Jan 37

We previously reported that the pregnane X receptor (PXR) interferes with vitamin D receptor (VDR) target genes, notably CYP24, by targeting the same responsive elements. Since PXR and constitutive androstane receptor (CAR) share responsive elements in the promoter of their target genes, we wondered whether CAR also interferes with CYP24 expression. The current study shows that: (i) CAR-RXR heterodimer binds to and transactivates the proximal promoter of CYP24 (-1200/+22) and both VDRE-1 and VDRE-2 which control its expression in response to 1,25-dihydroxyvitamin D(3), (ii) androstanol an inverse agonist of hCAR inhibits transactivation of VDREs by hCAR, (iii) mutations of either VDRE-1 or -2 half sites inhibit hCAR-mediated transactivation, and (iv) in primary human hepatocytes (n =11) CITCO, a specific hCAR agonist, is an inducer of CYP24 as well as of CYP2B6 and CYP3A4 mRNAs. In conclusion, CAR/PXR and VDR bind to and transactivate the same response elements in CYP24 promoter.
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PMID:Constitutive androstane receptor-vitamin D receptor crosstalk: consequence on CYP24 gene expression. 1758 73

Phenobarbital (PB) induces or represses a wide spectrum of genes in rodent liver. Much less is known about its effects in human liver. We used pangenomic cDNA microarrays to analyze concentration- and time-dependent gene expression profile changes induced by PB in the well-differentiated human HepaRG cell line. Changes in gene expression profiles clustered at specific concentration ranges and treatment times. The number of correctly annotated genes significantly modulated by at least three different PB concentration ranges (spanning 0.5 to 3.2 mM) at 20 h exposure amounted to 77 and 128 genes (p< or =0.01) at 2- and 1.8-fold filter changes, respectively. At low concentrations (0.5 and 1 mM), PB-responsive genes included the well-recognized CAR- and PXR-dependent responsive cytochromes P450 (CYP2B6, CYP3A4), sulfotransferase 2A1 and plasma transporters (ABCB1, ABCC2), as well as a number of genes critically involved in various metabolic pathways, including lipid (CYP4A11, CYP4F3), vitamin D (CYP24A1) and bile (CYP7A1 and CYP8B1) metabolism. At concentrations of 3.2 mM or higher after 20 h, and especially 48 h, increased cytotoxic effects were associated with disregulation of numerous genes related to oxidative stress, DNA repair and apoptosis. Primary human hepatocyte cultures were also exposed to 1 and 3.2 mM PB for 20 h and the changes were comparable to those found in HepaRG cells treated under the same conditions. Taken altogether, our data provide further evidence that HepaRG cells closely resemble primary human hepatocytes and provide new information on the effects of PB in human liver. These data also emphasize the importance of investigating dose- and time-dependent effects of chemicals when using toxicogenomic approaches.
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PMID:Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. 1908 49

To estimate the prostate cancer risk conferred by individual single nucleotide polymorphisms (SNPs), SNP-SNP interactions, and/or cumulative SNP effects, we evaluated the association between prostate cancer risk and the genetic variants of 12 key genes within the steroid hormone pathway (CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1). A total of 116 tagged SNPs covering the group of genes were analyzed in 2,452 samples (886 cases and 1,566 controls) in three ethnic/racial groups. Several SNPs within CYP19 were significantly associated with prostate cancer in all three ethnicities (P = 0.001-0.009). Genetic variants within HSD3B2 and CYP24A1 conferred increased risk of prostate cancer in non-Hispanic or Hispanic Caucasians. A significant gene-dosage effect for increasing numbers of potential high-risk genotypes was found in non-Hispanic and Hispanic Caucasians. Higher-order interactions showed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = 0.001). In African Americans, a 10-locus model, with SNPs located within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1, showed a significant interaction (P = 0.014). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < 0.001). These data are consistent with a polygenic model of prostate cancer, indicating that multiple interacting genes of the steroid hormone pathway confer increased risk of prostate cancer.
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PMID:Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. 1950 20

The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D(3) (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time PCR, we identified curcumin (CM), a turmeric-derived bioactive polyphenol, as a likely additional novel ligand for VDR. CM (10(-5) M) activated transcription of a luciferase plasmid containing the distal vitamin D responsive element (VDRE) from the human CYP3A4 gene at levels comparable to 1,25D (10(-8) M) in transfected human colon cancer cells (Caco-2). While CM also activated transcription via a retinoid X receptor (RXR) responsive element, activation of the glucocorticoid receptor (GR) by CM was negligible. Competition binding assays with radiolabeled 1,25D confirmed that CM binds directly to VDR. In mammalian two-hybrid assays employing transfected Caco-2 cells, CM (10(-5) M) increased the ability of VDR to recruit its heterodimeric partner, RXR, and steroid receptor coactivator-1 (SRC-1). Real-time PCR studies revealed that CM-bound VDR can activate VDR target genes CYP3A4, CYP24, p21 and TRPV6 in Caco-2 cells. Numerous studies have shown chemoprotection by CM against intestinal cancers via a variety of mechanisms. Small intestine and colon are important VDR-expressing tissues where 1,25D has known anticancer properties that may, in part, be elicited by activation of CYP-mediated xenobiotic detoxification and/or up-regulation of the tumor suppressor p21. Our results suggest the novel hypothesis that nutritionally-derived CM facilitates chemoprevention via direct binding to, and activation of, VDR.
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PMID:Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. 2015 25


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