Vitamin D 25-hydroxylase – Four decades of searching, are we there yet?

Zhu, Jinge; DeLuca, Hector F.

doi:10.1016/j.abb.2012.01.013

Cited by 158 publications

(118 citation statements)

References 101 publications

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“…Some of the candidates hypothesized earlier have been deemed less likely to be the physiological vitamin D 25-hydroxylase, at least in humans. For example, CYP2C11, the first isolated enzyme that contains vitamin D 25-hydroxylation activity, is only found in rat and is only present in males, with its major function being testosterone hydroxylase (4). Similarly, porcine CYP2D25 does not have a functionally related human ortholog.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, porcine CYP2D25 does not have a functionally related human ortholog. CYP2D6, the only P450 isoform of human CYP2D subfamily, exhibits no detectable vitamin D 25-hydroxylation activity despite 77% sequence identity (4). The species specificity and sexual dimorphism makes them less relevant as potential 25-hyroxylases.…”

Section: Discussionmentioning

confidence: 99%

“…Serum calcium was determined by atomic absorption at 422.7 nm on a Perkin-Elmer AA3110 spectrometer after diluting serum in 0.1% LaCl 3 solution. Serum phosphorus was determined using a colorimetric assay, in which serum was mixed with ammonium molybdate and malachite green to form a chromogenic complex measured at 660 nm (58 4 and 450 μL of CH 3 OH, with vortexing after the addition of each component. The supernatant was extracted with hexane and methyl t-butyl ether.…”

Section: Methodsmentioning

confidence: 99%

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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.

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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%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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.

Self Cite

271

140

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“…−/− mice only display a 50 % reduction in serum 25(OH)D compared with wildtype or heterozygous animals, suggesting that other enzymes help maintain circulating 25(OH)D levels and/ or compensate for CYP2R1 dysfunction (30) . In human subjects, other P450 cytochromes such as CYP3A4 (31) , CYP2J2 (32) and CYP27A1 (33) display 25-hydroxylase activity towards VD molecules, but less efficiently (i.e.…”

Section: -Hydroxylationmentioning

confidence: 99%

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

et al. 2015

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Cross-sectional studies depict an inverse relationship between vitamin D (VD) status reflected by plasma 25-hydroxy-vitamin D and obesity. Furthermore, recent studies in vitro and in animal models tend to demonstrate an impact of VD and VD receptor on adipose tissue and adipocyte biology, pointing to at least a part-causal role of VD insufficiency in obesity and associated physiopathological disorders such as adipose tissue inflammation and subsequent insulin resistance. However, clinical and genetic studies are far less convincing, with highly contrasted results ruling out solid conclusions for the moment. Nevertheless, prospective studies provide interesting data supporting the hypothesis of a preventive role of VD in onset of obesity. The aim of this review is to summarise the available data on relationships between VD, adipose tissue/adipocyte physiology, and obesity in order to reveal the next key points that need to be addressed before we can gain deeper insight into the controversial VD-obesity relationship.Adipose tissue: Vitamin D: Obesity: Inflammation: Adipocytes: Nutrients: Nutrition Vitamin D: a brief overview Vitamin D (VD; calciferol) is a hormone mainly described for its role as a regulator of phosphate and calcium homeostasis (1) . It can be obtained through animal (VD 3 , cholecalciferol) or plant (VD 2 , ergocalciferol) food sources. Only a few foodstuffs contain significant amounts of VD, the main sources being fish liver oils, fatty fish (sardines, herring and mackerel) and egg yolk (2,3) , but small quantities are also found in fortified milk, orange juice, bread and cereals. Alternatively, VD 3 is produced endogenously in the skin after UVB irradiation from the precursor 7-dehydrocholesterol to give pre-VD 3 , which is further isomerised to VD 3 before being released into the circulation (4) . Classical estimates have assigned a majority (70-90 %) of VD supply to dermal synthesis, but a recent paper revised this figure down to just 10-25 % of VD supply (5) and posited that dietary intake of 25-hydroxy-vitamin D (25(OH)D) is a significant contributor to total VD input.Adipose tissue is a major storage site for vitamin D Despite limited data, it is widely accepted that adipose tissue is a reservoir for VD in human subjects and rats (6)(7)(8)(9)(10) . Interestingly, visceral fat was found to contain 20 % more VD than subcutaneous fat (11) . Heaney et al. (12) calculated that 65 % of total VD in the body is in the form of D 3 , for which adipose tissue and skeletal muscle appear to be the main body stores (accounting for 73 and 16 %, respectively).

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“…drugs) are known, there are few good examples of similar activity with endogenous compounds (including vitamins), and some of these may be the result of chemical reactivity more than specific binding. 25-Hydroxylation of vitamin D 3 is catalyzed by a number of P450s (74). Another example is retinoic acid 4-hydroxylation (75), which may be due in part to the chemical proclivity of oxidation at the allylic position.…”

Section: Discussionmentioning

confidence: 99%

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

Pallan

Nagy

Lei

et al. 2015

Journal of Biological Chemistry

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Background: Fish (and human) P450 17A1 catalyze both steroid 17␣-hydroxylation and 17␣,20-lyase reactions. A second fish P450, 17A2 (51% identical), catalyzes only 17␣-hydroxylation. Results: Crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1 are very similar. Conclusion: In kinetic analysis, the two-step oxidation of progesterone is more distributive than for pregnenolone. Significance: Small structural differences are associated with activities of the two fish P450s.

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Vitamin D 25-hydroxylase – Four decades of searching, are we there yet?

Cited by 158 publications

References 101 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

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

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