Vit D (calciferol)

Hydroxylase rxns: mixed-function oxidases

(the enzymes reduce one atom of molecular oxygen to water and one to the hydroxyl group).

Toxicity

-50 mg -the most likely of all vitamins to cause a toxicity -excessive exposure in the sun doesnt overproduce

Vit D active forms/chemical structures

-D2 (ergocalciferol) -D3 (cholecalciferol) -provitamin : 7 dehydrocholestrol

Vit D functions

-Functions due to Vitamin D receptor mediation -Regulation of gene expression -Differentiation of stem cells in bone tissue -Differentiation of hair follicles and skin cells (from VDR/1,25-dihydroxycholecalciferol -Possible roles in bone metabolism and/or bone formation and cancer prevention or treatment -Multiple sclerosis, type 1 diabetes, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and rheumatoid arthritis -Thought to prevent heart diseases of various types

Vit D is unique because

-Is synthesized in the body with adequate sun exposure -Functions as a hormone (because it is dependent on interacting with a receptor) -it increases absorption of calcium

Role of PTH in the homeostatic control of calcium through interaction with Vit D metabolism

-Low blood calcium increases secretion of PTH. PTH stimulates: (1) calcium release from bone; (2) 1 α-hydroxylase to produce 1,25 (OH)2D3 (3) the reabsorption of calcium by the kidney tubules. 1,25 (OH)2 will enhance calcium absorption by stimulating small intestinal cells to produce the calcium uptake protein, calbindin. These series of reactions maintain calcium levels within a normal range.

Vit D metabolism and storage

-Metabolized to 25(OH)D in liver -25-OH D secreted into blood, transported by DBP -Converted to 1,25-OH2 D (calcitriol) in kidneys -Calcitriol released into blood

How Vit D exerts its actions on genes

-The vitamin D receptor (VDR) acts in partnership with the retinoic acid receptors (RXR) and binds to nucleotide base pairs called the vitamin D-responsive elements (VDRE) to control gene expression. -Cis-retinoic acid and 1,25-dihydroxycholecalciferol are ligands that must be present to control gene expression.

sources of Vit D

-UV light -Animal foods (eggs, liver, fatty fish, and butter) -Fortified milk and dairy products -Fortified margarine

Vit D absorption

-dietary vit D require no digestion -Absorbed from micelle by passive diffusion with help from fat and bile salts --incorporated into chylomicron for: • transport into lymphatic system, then blood • transferred to vitamin D binding proteins (DBP) to skeletal muscle and adipocytes

RDA notes

-recommended based on need to prevent bone disease -elderly have lessened sun exposure so they need more -practical: 15 minutes of sun/day

at risk defiency

-vegans, lactose intolerant

Deficiency

-widespread world wide -rickets in children - failure of bone to mineralize. bowing of long, weight bearing bones. -osteomalacia in adults - failure to mineralize already formed bone. results form decreased Ca and P absorption

KNOW THIS PATHWAY

1. low blood calcium initiates stimulus 2. signals PT gland to release PTH 3. increaseed PTH in blood 4. stimulates renal hydroxylase 25-OH D --> 1,25-OH2 D (calcitriol) 5. increased blood calcitriol; dietary Ca+ in lumen 6. calcitriol also stimulates kidneys to increase calcium reabsorption by increasing calbindin D28k synthesis 7.increases blood calcium 8. increases calcitriol stimulates Ca+ absorption in the intestine; increases calbindin D9k synthesis. 9. increases blood calcium 10. increased PTH, increased calcitriol travels to bone 11. increased PTH and calcitriol stimulate reabsorption of Ca+ and P from bone 12. End result: increased blood calcium

the body can produce Vit D3 from

7-dehydrocholesterol

older adults produce less

DHCR7 and therefore produce up to 75% less less vitamin D

The hydroxylation rxn

In the liver: -25-hydroxylase (NADPH-dependent), hydroxylates vitamin D3 at carbon 25 to form 25(OH)D. -Another 25-hydroxylase hydroxylates vitamin D3 as well as D2. It is not until hydroxylation at C-25 in the liver and C-1 in the renal cells lining the proximal tubule that the active form of vitamin D, 1,25-dihydroxycholcalciferol [1,25-(OH)D3] is produced.

Functions and mechanisms of action

Serum calcium homeostasis: -effects on kidneys, small intestine, bone Calcitriol synthesis: -Stimulated in response to changes in serum calcium concentrations and the release of PTH •Normal serum calcium: 8.5-10.5 mg/dL (2.12-2.62 mmol/L) •Hypocalcemia (less than 8.5 mg/dL) Phosphorus Homeostasis -•Calcitriol enables phosphorus absorption in the intestine -Calcitriol promotes resorption of phosphorus out of bone and into blood

ergosterol, 7-dehydrocholesterol

The 2 forms of naturally occurring provitamin D -are both 4 ring sterols which are a characteristic of a steroid

Vit D2 (ergoferol) is produced via

UV irradiation of ergosterol

most supplements are

Vit D3, but some still use D2. D2 form is less potent

Vitamin D3 is created photochemically as UV light converts the precursor sterol 7-dehydrocholeserol to

cholecalciferol. That reaction takes place as sebaceous glands secret 7-dehydrocholesterol onto the skins surface. Cholecalciferol can then be reabsorbed to varying depths within the skin

Vitamin D reaching the liver either by way of chylomicron remnants or by DBP must be hydroxylated by

cytochrome P-450 hydroxylases to begin the generation of vitamin D's active form.

As long as humans receive adequate exposure to sunlight, dietary vitamin D may not be needed. However, because adequate exposure to sunlight is recommended to decrease the risk of skin cancer,

dietary vitamin D is still deemed essential

Vitamin D3 (cholecalciferol) is produced by

irradiating 7-dehydrocholesterol (a provitamin in skin) from UV light.

•Ergocalciferol:

known as vitamin D2 or calciferol, found in food and as dietary supplement (3 ring structure with one broken ring)

•Cholecalciferol:

known as vitamin D3, made by the skin when exposed to light (3 ring structure with one broken ring)

Hydroxylation reactions of vitamin D biological significance

-Hydroxylation in the liver and renal cells -- active form of vitamin D, 1,25-dihydroxycholcalciferol [1,25-(OH)D3] is produced.

Calcitriol acts on cells in the gastrointestinal tract to increase the production of calcium transport proteins,

termed calbindin-D proteins, which results in increased uptake of calcium from the gut into the body. This is the only mechanism by which the body can increase its calcium stores.

The efficiency of vitamin D binding is tremendously increased after

two hydroxylations to its molecular form. (from the liver and the kidney) Liver - vitamin is hydroxylated at carbon 25 by 25 hydroxylase.

If the body needs calcictriol (when we have low levels of calcium in the blood):

PTH is released, 25(OH)D -->kidneys --> calcitriol