INT262123

Context Info Confidence 0.67 First Reported 2009 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 17 Total Number 20 Disease Relevance 6.67 Pain Relevance 1.38

mitochondrion (Cyp24a1) oxidoreductase activity (Cyp24a1)

Anatomy Link Frequency liver 3 intestine 3 kidney 3 Cyp24a1 (Mus musculus)

Pain Link Frequency Relevance Heat agonist 148 99.20 Inflammation 272 96.32 antiepileptic Drug 16 87.76 carbamazepine 16 82.96 Bile 688 78.36 Inflammatory stimuli 16 68.96 anticonvulsant 16 53.60 antagonist 112 5.00 Crohn's disease 96 5.00 antidepressant 48 5.00

Disease Link Frequency Relevance Heat Targeted Disruption 420 99.16 Rickets 200 98.58 Inflammatory Bowel Disease 512 96.32 INFLAMMATION 192 90.32 Infection 32 88.96 Metabolic Bone Disease 16 85.36 Obesity 68 79.84 Disease 184 79.60 Extrahepatic Cholestasis 4 73.84 Pancreatic Cancer 4 70.88

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

The increased Fgf23 suppresses the expression of Cyp27b1 and induces the expression of Cyp24 by activating the ?

Gene_expression (expression) of Cyp24

1) Confidence 0.67 Published 2010 Journal Cell Tissue Res Section Body Doc Link PMC2948652 Disease Relevance 0.20 Pain Relevance 0.10

The Fgf23 suppresses the expression of Cyp27b1 and induces the expression of Cyp24 in the kidney (Shimada et al 2004).

Gene_expression (expression) of Cyp24 in kidney

2) Confidence 0.52 Published 2010 Journal Cell Tissue Res Section Body Doc Link PMC2948652 Disease Relevance 0.23 Pain Relevance 0.03

Cyp27b1 and Cyp24 encode enzymes, 1a-hydroxylase and 24-hydroxylase, which synthesize and inactivate active vitamin D, respectively.

Gene_expression (synthesize) of 24-hydroxylase

3) Confidence 0.52 Published 2010 Journal Cell Tissue Res Section Body Doc Link PMC2948652 Disease Relevance 0.26 Pain Relevance 0

The suppression of Cyp27b1 expression and induction of Cyp24 expression by Fgf23 result in decreased levels of active vitamin D in serum.

Gene_expression (expression) of Cyp24

4) Confidence 0.52 Published 2010 Journal Cell Tissue Res Section Body Doc Link PMC2948652 Disease Relevance 0.33 Pain Relevance 0.03

In addition, CYP24 is expressed at very low levels in liver and intestine where SXR is abundant [Xu et al., 2006].

Gene_expression (expressed) of CYP24 in intestine

5) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.41 Pain Relevance 0.05

However, this model is of questionable significance with regard to the physiological functions of CYP24 in vivo, because CYP24 is found primarily in the kidney, where SXR is expressed at very low levels.

Gene_expression (found) of CYP24 in kidney

6) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.42 Pain Relevance 0.06

This provided a mechanism to explain the low levels of CYP24 expression in tissues containing high levels of SXR. 1,25(OH)2D3-induced CYP24 expression was enhanced in SXR knockout mice, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite marked CYP3A4 induction [Zhou et al., 2006a].

Gene_expression (expression) of CYP24 associated with targeted disruption and agonist

7) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.15 Pain Relevance 0.05

It upregulates CYP3A4 expression, while repressing CYP24 and CYP2D25 expression in the liver and intestine.

Gene_expression (expression) of CYP24 in intestine

8) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.68 Pain Relevance 0.18

To reveal the mechanism of drug-induced osteomalacia, several groups recently investigated the impact of SXR activation on CYP24 gene expression in vitro and in vivo.

Gene_expression (expression) of CYP24 gene associated with rickets

9) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.44 Pain Relevance 0.08

Furthermore, feeding WT mice with diet containing the mouse SXR ligand, PCN, for two weeks strongly induced SXR target genes CYP3A11, GSTA1, and MDR1a expression, but failed to induce CYP24 expression in both liver and intestine (Zhou, C., unpublished observation).

Gene_expression (expression) of CYP24 in intestine

10) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.21 Pain Relevance 0.04

This suggests that enhanced CYP24 expression by SXR is unlikely to play an important role in the development of osteomalacia following long-term treatment with SXR activators.

Gene_expression (expression) of CYP24 associated with rickets

11) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.40 Pain Relevance 0

It was later shown that activation of SXR did not induce CYP24 expression in vitro or in vivo, nor did it transactivate the CYP24 promoter [Zhou et al., 2006a].

Gene_expression (expression) of CYP24

12) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.14 Pain Relevance 0.03

Pascussi et al. first suggested that activation of SXR can enhance the expression of the VDR target gene, CYP24, which would increase the catabolism of 1,25(OH)2D3; thereby, leading to drug-induced osteomalacia [Pascussi et al., 2005].

Gene_expression (expression) of CYP24 associated with rickets

13) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.44 Pain Relevance 0.08

This provided a mechanism to explain the low levels of CYP24 expression in tissues containing high levels of SXR. 1,25(OH)2D3-induced CYP24 expression was enhanced in SXR knockout mice, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite marked CYP3A4 induction [Zhou et al., 2006a].

Gene_expression (expression) of CYP24 associated with targeted disruption and agonist

14) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.15 Pain Relevance 0.05

They conducted a series of in vitro and in vivo studies which were interpreted as providing evidence that a drug, which can activate SXR is likely to enhance CYP24 expression and the catabolism of 25(OH)D3, leading to vitamin D deficiency.

Gene_expression (expression) of CYP24

15) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.44 Pain Relevance 0.06

Although there is also a relatively high level of VDR expression in the small intestine, constitutive CYP24 expression in this tissue is very low or undetectable, in contrast to that in the kidney [Xu et al., 2006].

Gene_expression (expression) of CYP24 in kidney

16) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.33 Pain Relevance 0.21

This provided a mechanism to explain the low levels of CYP24 expression in tissues containing high levels of SXR. 1,25(OH)2D3-induced CYP24 expression was enhanced in SXR knockout mice, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite marked CYP3A4 induction [Zhou et al., 2006a].

Gene_expression (expression) of CYP24 associated with targeted disruption and agonist

17) Confidence 0.44 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.15 Pain Relevance 0.05

In addition, CYP24 is expressed at very low levels in liver and intestine where SXR is abundant [Xu et al., 2006].

Gene_expression (expressed) of CYP24 in liver

18) Confidence 0.15 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.41 Pain Relevance 0.05

Furthermore, feeding WT mice with diet containing the mouse SXR ligand, PCN, for two weeks strongly induced SXR target genes CYP3A11, GSTA1, and MDR1a expression, but failed to induce CYP24 expression in both liver and intestine (Zhou, C., unpublished observation).

Gene_expression (expression) of CYP24 in liver

19) Confidence 0.15 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.21 Pain Relevance 0.04

It upregulates CYP3A4 expression, while repressing CYP24 and CYP2D25 expression in the liver and intestine.

Gene_expression (expression) of CYP24 in liver

20) Confidence 0.15 Published 2009 Journal Nuclear Receptor Signaling Section Body Doc Link PMC2646121 Disease Relevance 0.68 Pain Relevance 0.18

General Comments

This test has worked.