Vitamin D 25-hydroxylase

VISCOSITY COEFFICIENT VITAMIN A GROUP VITAMIN D GROUP VITAMIN D 25-HYDROXYLASE VITAMIN K-DEPENDENT y-GLUTAMYL CARBOXYLASE... 

Vitamin D2 and vitamin D3 are metabolized to 2 5-hydroxy-vitamin D [25(OH)D] by vitamin D-25-hydroxylase, a cytochrome P450 enzyme, in liver (Figure 49. 

There are two hepatic vitamin D 25-hydroxylases, the major one in the mitochondria and the other in the smooth endoplasmic reticulum (Figure 37-2). Both require NADPH and molecular oxygen. The microsomal enzyme appears to be a P-450 mixed-function oxidase. 25-Hydroxylase activity also occurs in intestine, kidney, and lung. 25-Hydroxylase is apparently regulated only by availability of its substrate, leading to a high plasma concentration of 25-(OH)D and a low concentration of vitamin D. 

C. Theodoropoulos, R. Lapointe, G. Jones et al. (2001). Expression of CYP27A, a gene encoding a vitamin D-25 hydroxylase in human liver and kidney. Clin. Endocrinol. (Oxford) 54, 107-115. 

Derived from cholesterol, vitamin D is biosynthesized from its prohormone cholecalciferol (Ds), the product of solar ultraviolet irradiation of 7-dehydrocholesterol in the skin (2). In 1966, it was first recognized that vitamin D must undergo activation via two oxidative metabolic steps (Fig. 35.2). The first oxidation to 25-hydroxycholecalciferol (25(OH)D3 calcifediol Calderol) occurs in the endoplasmic reticulum of the liver and is catalyzed by vitamin D 25-hydroxylase. This activation step is not... 

Vitamin D-25-hydroxylase of rat liver is a mixed function monooxygenase as demonstrated by the incorporation of 2 into the 25 position of vitamin D The reaction is inhibited by metyrapone, and C0 02 of 9 1. The CO inhibition is released with white light. Vitamin D inhibits aminopyrine demethylase. Thus all evidence currently available suggests this to be a cytochrome P-450 system of the type shown in Fig. 3. Phenobarbital does not induce the vitamin D-25-hydroxylase despite claims to the contrary (T. Madhok and H. F. DeLuca, unpublished re-... 

Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanizalion of eytoehrome P450 2R1 a microsomal vitamin D 25-hydroxylase. J Biol Chem 278 38084-38093... 

Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101 7711-7715... 

Zhu J, DeLuca HE (2012) Vitamin D 25-hydroxylase—four decades of searching, are we there yet Arch Biochem Biophys 523 30-36... 

Figure 4 A schematic representation of the origin of vitamin D3 and its metabolism in the liver by the hepatic vitamin D-25-hydroxylase. Once formed, the 25-hydroxyvitamin D3 (25(OH)D3> is metabolized by either a 25(OH)D-1a-hydroxylase or a 25(OH)D-24-hydroxylase. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) can either go to its target tissues to carry out its biologic functbn(s), or it can be metabolized in its side-chain and degraded to calcitroic add. (Reproduced with permissbn from Holick MF (1995) Vitamin D Photobiology, Metabolism, and Clinical Applications. In DeGroot U etal. (eds.) Endocrinology, 3rd edn, pp. 990-1013. Philadelphia W.B. Saunders.)...

Ren S, Nguyen L, Wu S, Encinas C, Adams JS, et al. 2005. Alternative splicing of vitamin D-24-hydroxylase a novel mechanism for the regulation of extrarenal 1,25-dihydrox-yvitamin D synthesis. J Biol Chem 280 20604-20611. 

Sterol-specific cytoplasmic receptor proteins (vitamin D receptor) mediate the biological action of vitamin D (9). The active hormone is transported from the cytoplasm to the nucleus via the vitamin D receptor, and as a result of the interaction of the hormone with target genes, a variety of proteins are produced that stimulate the transport of calcium in each of the target tissues. Active vitamin D works in concert with PTH to enhance active intestinal absorption of calcium, to stimulate bone resorption, and to prohibit renal excretion of calcium (2,9). If serum calcium or 1,25-calcitriol concentrations are elevated, then vitamin D 24-hydroxylase (in renal mitochondria) is activated to oxidize 25(OH)D3 to inactive 24,25-dihydroxy-cholecalciferol and to further oxidize active vitamin D to the inactive 1,24,25-trihydroxylated derivative. Both the 1,24,25-trihydroxylated and the 24,25-dihydroxylated products have been found to suppress PTH secretion as well. Several factors have been identified in the regulation of the biosynthesis of vitamin D, including low phosphate concentrations (stimulatory) as well as pregnancy and lactation (stimulatory). 

Deficient la-hydroxylase activity, characterized by the infantile onset of severe hypocalcemia, moderate hypophosphatemia, and responsiveness to pltysiologic doses of calcitriol, has been called hereditary pseudo-vitamin D deficiency rickets (PDDR), vitamin D dependency because of its responsiveness to active vitamin D, or vitamin D-dependent rickets type 1. This disease is now more simply and appropriately termed vitamin D la-hydroxylase deficiency. Affected persons are normal at birth but have growth retardation, poor motor development, arrd generalized muscle weakness by 2 years of age. Affected children develop hypocalcerrria, hypophosphatemia, increased seram alkaline phosphatase activity, and increased seram PTH some develop hypocalcerrric seizures. Serum concentratiorrs of 1,25(0H)2D are low despite normal concerrtra-tions of 250HD responses to administration of 1,25(0H)2D are excellent. 

Fu GK, Lin D, Zhang MYH, Bikle DD, Shackleton CHL, Miller WL, Poitale AA(1997) Cloning of human 25-hydroxy vitamin D-la-hydroxylase and mutations causing vitamin D-dependant rickets type I. Mol Endocrinol 11 1961 1970... 

Vitamin D must undergo two hydroxylation steps before it can function on the target cells. The first hydroxylation to 25-hydroxy vitamin D (25-OHD) occurs in the liver, from whence the 25-OHD is transported to the kidney bound to a carrier protein. In the kidney a second hydroxylation is carried out by a 25-hydroxy vitamin D-la-hydroxylase to yield 1,25-dihydroxy vitamin D (1,25-(OH)2D) which... 

Metabolites of vitamin D, eg, cholecalciferol (CC), are essential in maintaining the appropriate blood level of Ca ". The active metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC), is synthesized in two steps. In the fiver, CC is hydroxylated to 25-hydroxycholecalciferol (25-HCC) which, in combination with a globulin carrier, is transported to the kidney where it is converted to 1,25-DHCC. This step, which requites 1-hydroxylase formation, induced by PTH, may be the controlling step in regulating Ca " concentration. The sites of action of 1,25-DHCC are the bones and the intestine. Formation of 1,25-DHCC is limited by an inactivation process, ie, conversion of 25-HCC to 24,25-DHCC, catalyzed by 24-hydroxylase. 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

CYP24 is a 25-hydroxyvitamin D3 24-hydroxylase that degrades vitamin D metabolites. 

Stimulating activation of vitamin D by 1-a-hydroxylase to cal-citriol (1,25-dihydroxyvitmin D3) to promote calcium absorption in the GI tract and increased calcium mobilization from bone... 

Lead has been shown to decrease circulating levels of the active form of vitamin D (1,25-dihydroxy-vitamin D) in children. The conversion of vitamin D to this active hormonal form takes place via hydroxylation to 25-hydroxyvitamin D in the liver, followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 (heme-containing) system (Mahaffey et al. 1982 Rosen and Chesney 1983). Comparisons of the serum 1,25-dihydroxyvitamin D levels in children with blood lead levels of 33 g/dL with those in children with severe renal insufficiency (Rosen et al. 1980) and in children with an inborn error of vitamin D metabolism in which the 1-hydroxylase system or component... 

There seems to be no metabolic control exerted on hepatic 25-hydroxylase and so all of the available cholecalciferol is converted. Hydroxylation in the kidney however is an important control point being regulated by PTH, and indirectly therefore by calcium and phosphate concentrations. Stimulation of la-hydroxylase by PTH is via a cyclic AMP (cAMP) -dependent mechanism and longer-term regulation of the activity of this enzyme is via induction mediated by other hormones such as oestrogens, cortisol and growth hormone. Typically, the plasma concentration of 1,25 dihydroxy vitamin D is in the range 20-60 ng/1, that is approximately 1000-times lower than that of its precursor. 

When 1,25 DHCC provision is adequate or when plasma calcium concentration is above approximately 2.20mmol/l, la hydroxylase activity is suppressed and 25-hydroxy vitamin D3 is converted by 24-hydroxylase into 24,25 dihydroxy vitamin D3 a metabolite whose true role is uncertain but one which seems to have little if any physiological activity. Renal 24-hydroxylase does have a role to play in the deactivation of 1,25 dihydroxy vitamin D the major metabolite of the vitamin being 1,24,25 trihydroxy vitamin D. 

Vitamin D deficiency may also occur through inadequate dietary intake, gut (poor absorption), renal disease (1-hydroxylase deficiency or failure to reclaim calcium from the glomerular filtrate), or liver disease (25-hydroxylase deficiency). The slightly low haemoglobin concentration and pale stained (hypochromic) red cells suggested a coincident mild iron deficiency. 

Danan JL, Delorme AC, Mathieu H. 1982. Presence of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 24-hydroxylase in vitamin D target cells of rat yolk sac. J Biol Chem 257 10715-10721. 

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