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