Vitamin D3

[Ref: AV6:chp10; WG21:chp21]

Aka cholecalciferol

Production

Step 1 - Skin

Derived from cholesterol

7-dehydrocholesterol in skin

--> Formation of Vitamine D3 (cholecalciferol) by UV radiation

--> Transport in plasma bound to vitamin D-binding protein (DBP)

Step 2 - Liver

Hydroxylation of vitamine D3

--> 25-hydroxycholecalciferol (aka calcidiol)

Enzyme: 25-hydroxylase

Step 3 - Kidney

Proximal tubular cells hydroxylate 25-hydroxycholecalciferol

--> 1,25-dihydroxycholecalciferol AND 24,25-dihydroxycholecalciferol

Enzyme: 1alpha-hydroxylase and 24-hydroxylase

NB:

1,25-dihydroxycholecalciferol
= Active

24,25-dihydroxycholecalciferol
= Less active

1,25-dihydroxycholecalciferol

aka calcitriol or 1,25-(OH)2D3

Active metabolite

Also produced in the placenta, keratinocytes, macrophages

NB:

• Vitamine D2 (ergocalciferol) is ingested in food, specifically food derived from plants

Actions

Mechanism of action

Binding of receptor

--> Increased transcription of some mRNA

--> Increase formation of calbindin-D proteins

Calbindin-D proteins

Two types

• Calbindin-D9k
  * Binds 2 Ca2+
• Calbindin-D28k
  * Binds 4 Ca2+ (even though it has 6 binding sites)

Increased calbindin-D levels

--> Increased Ca2+ transport

[WG21:p392] Exact mechanism still uncertain

Ca-H ATPase pump

Some evidence that calcitriol increases the number of Ca2+-H+ ATPase pump in intestinal cells

--> Increased transport

Actions

• Stimulate intestinal absorption of Ca2+ and PO4
  * Main action
• Stimulate renal reabsorption of Ca2+ and PO4

Other actions

Increase synthetic activity of osteoblasts

Necessary for normal calcification of matrix

Probably also stimulates differentiation of immune cells and keratinocytes in skin

 

Regulation

• Formation of 25-hydroxycholecalciferol is not regulated
• Formation of 1,25-dihydroxycholecalciferol is

Factors affecting 1,25-dihydroxycholecacliferol formation

Factors increasing formation

• PTH
  * Increase activity of 1alpha-hydroxylase
• Low PO4
  * PO4 inhibits 1alpha-hydroxylase
• High level of 1,25-(OH)2D3
  * i.e. direct negative feedback
  * This negative feedback also inhibits PTH and thus inhibit 1,25-(OH)2D3 indirectly as well

Also

• Low Ca2+
  * indirectly via PTH
• Prolactin
  * Thus 1,25-(OH)2D3 level elevated in pregnancy
  * But probably only increase DBP and thus free D3 stays unchanged
• Growth hormone
• hCS
• Calcitonin

NB:

• When 1alpha-hydroxylase activity is decrease,
  --> Increased formation of 24,25-dihydroxycholecalciferol
  * 24-hydroxylase not regulated and not inhibited

Factors reducing formation

• Hyperthyroidism
• Metabolic acidosis