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CYP2R1 (vitamin D 25-hydroxylase ) semiactivates vitamin D in many places in the body

CYP2R1 cytochrome P450 family 2 subfamily R member 1 - Homo sapiens (human)  NCBI

Prefered name = vitamin D 25-hydroxylase

It performs the same first-phase of Vitamin D activation as the CYP27A1 in the liver
Second phase of activation is performed by CYP27B1 in the Kidney and other places in the body
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CYP2R1 Human Protein Atlas

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See also VitaminDWiki

Genetics category listing contains the following

245 articles in the Genetics category

see also 300 articles in Vitamin D Receptor, 113 articles in Vitamin D Binding Protein

Vitamin D blood test misses a lot
Blood Test Misses a lot (VDW 3439)

  • Snapshot of the literature by VitaminDWiki - (subject to many future developments)
  • Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, andi in 2017 is speculated to be 90%
  • Note: Good results from a blood test (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
  • A Vitamin D test in cells appears feasible (personal communication)
    However test results would vary in each tissue due to multiple genes
  • Good clues that Vitamin D is being restricted from getting to the cells
    1) A vitamin D-related health problem runs in the family
       especially if it is one of 51+ diseases related to Vitamin D Receptor
    2) Slightly increasing Vitamin D show benefits (even if conventional Vitamin D test shows an increase)
    3) Vitamin D Receptor test (<$30) scores are difficult to understand in 2016
        easier to understand the VDR 23andMe test results analyzed by FoundMyFitness in 2018
    4) Back Pain
        probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc
          The founder of VitaminDWiki took action with clues #3&4

Poor CYP2R1 associated with 1.4 X higher risk of low vitami D - Meta-analysis Aug 2018

Effects of CYP2R1 gene variants on vitamin D levels and status: A systematic review and meta-analysis.
Gene. 2018 Aug 15. pii: S0378-1119(18)30918-1. doi: 10.1016/j.gene.2018.08.056
Duan L1, Xue Z1, Ji H1, Zhang D2, Wang Y3.

BACKGROUND AND OBJECTIVE:
CYP2R1 is a key gene in the vitamin D metabolic pathway. It has been suggested that CYP2R1 gene variants in European populations are associated with concentrations of 25(OH)D, a biomarker of vitamin D levels and status in peripheral blood. However, a comprehensive meta-analysis of this effect including different ethnicities has never been conducted. The objective of this meta-analysis was to evaluate the association between CYP2R1 gene variants and 25(OH)D levels and vitamin D status.

METHODS:
PubMed, EMBASE, Web of Science, CNKI and Wanfang databases were systematically searched up to May 2018. Reporting followed PRISMA guidelines. The quality of the evidence was assessed using the STREGA system. Random or fixed effects model combined estimates and sub-group tested for ethnic differences. The I2 statistic quantified between-study variation due to heterogeneity.

RESULTS:
Sixteen articles with a total of 52,417 participants met the inclusion criteria and were included in the meta-analysis. For rs10741657, GG genotype was associated with a clear descending trend of 25(OH)D levels when compared with the AA genotype [SMD = -2.32, 95% CI (-4.42, -0.20); SMD = -3.46, 95% CI (-6.60, -0.33) and SMD = -0.24, 95% CI (-0.51, -0.03) for total, Caucasian and Asian groups, respectively] with the following heterogeneities I2 = 37.9%, 69.2% and 24.5%, respectively. However, under the AG/AA genetic model, significant changes in 25(OH)D levels [SMD and 95% CI: -1.27(-2.32, -0.23)] were only evident in the Caucasian population. The meta-analysis on vitamin D deficiency showed that the risk-allele G was associated with an increased risk of vitamin D deficiency (OR = 1.09; 95% CI = 1.03-1.15, P = 0.002).
The association between rs10741657 and increased risk of vitamin D deficiency was significant (OR = 1.42; 95% CI = 1.11-1.83, P = 0.006) under the dominant model (GG + AG/AA), but not under the recessive model (GG/AG + AA), (OR = 1.28; 95% CI = 0.89-1.84, P = 0.181). There was no evidence of publication bias.

CONCLUSION:
Published articles provide evidence supporting a major role for the rs10741657 polymorphism of the CYP2R1 gene in determining 25(OH)D levels and the presence of vitamin D deficiency.
PDF is available free at Sci-Hub  10.1016/j.gene.2018.08.056


CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo – Sept 2013

Proc Natl Acad Sci U S A. 2013 Sep 24; 110(39): 15650–15655. online 2013 Sep 9. doi: 10.1073/pnas.1315006110
PMCID: PMC3785760
Jinge G. Zhu,a Justin T. Ochalek,a Martin Kaufmann,b Glenville Jones,b and Hector F. DeLucaa,1
 Download the PDF from VitaminDWiki

SIGNIFICANCE
Although the vitamin D endocrine system has been well defined and the enzyme responsible for converting 25-hydroxyvitamin D to the final hormone, 1α,25-dihydroxyvitamin D3, is well understood, the enzyme responsible for the conversion of vitamin D to the blood form, 25-hydroxyvitamin D, has not been clearly identified. A case has been made for vitamin D 25-hydroxylase CYP2R1 as the responsible enzyme, but proof is lacking. We have produced a null mutant mouse lacking CYP2R1. With this model, we have shown that CYP2R1 is the major but not exclusive 25-hydroxylase and that there remains another significant enzyme responsible for this step in vitamin D activation that has yet to be identified.

ABSTRACT
Bioactivation of vitamin D consists of two sequential hydroxylation steps to produce 1α,25-dihydroxyvitamin D3. 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 D3. Curiously, the 1α,25-dihydroxyvitamin D3 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 D3 and 1α,25-dihydroxyvitamin D3. 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.

The active vitamin D hormone, 1α,25-dihydroxyvitamin D, plays a pivotal role in calcium homeostasis and phosphate metabolism, and is likely involved in other biological actions such as the immune system (1-3). 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is synthesized from vitamin D3 in two sequential steps in vivo. The production of 25-hydroxyvitamin D3 [25(OH)D3], the major circulating form of vitamin D3, occurs predominantly in the liver (4). The final activation step occurs largely in the proximal convoluted tubule of the kidney to produce 1,25(OH)2D3 (5).

25-Hydroxyvitamin D 1a-hydroxylase CYP27B1 (CYP27B1) has long been identified as the sole 25(OH)D3 1α-hydroxylase in a number of species, including human (5), whereas the specific vitamin D3 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 (8–14). However, it is a low-affinity, 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)D3 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)D3 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 D3 and vitamin D2 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 having 25(OH)D3 deficiency (22–26). These patients exhibited symptoms of vitamin D-dependent rickets. This condition appeared to mostly result from an amino acid mutation (Leu99Pro) that altered the CYP2R1 structure and abolished 25-hydroxylase activity (21), although other mutations have been reported (26).

We have created CYP2R1−/− and CYP2R1/Cyp27a1 double-knockout mouse models and evaluated the physiological role of CYP2R1 in the vitamin D activation pathway. Our results strongly support the concept that CYP2R1 is a major contributor to 25-hydroxylation of vitamin D in vivo, but show there is another unidentified enzyme that participates in this important activation.

Created by admin. Last Modification: Friday February 22, 2019 14:56:43 GMT-0000 by admin. (Version 13)

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8561 CYP2R1 is a major.pdf admin 18 Oct, 2017 01:39 1.03 Mb 130
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8559 CYP2R1 locations.jpg admin 18 Oct, 2017 00:04 42.37 Kb 290
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