This is a summary of the journal : 'Is there more to learn about functional vitamin D metabolism?' presented by my friend Svenia and me. Hope it helps.

1. Is there more to learn about functional vitamin
D metabolism?
Presented by Nabiilah Naraino Majie and Svenia Joorawon
Date: 26.01.2016

2. Table of content
• Introduction
• Enzymes involved in functional metabolism
pathway
• Vitamin D receptor (VDR)
• Role of vitamin D in immune system
• Conclusion
• References

3. Introduction
• Vitamin D is a fat-soluble vitamin which has an essential role in the body.
It is metabolised to its biologically active forms to carry out its functions.
• In 1968, a more polar vitamin D was determined to achieve its functions
after handling unlabeled vitamin D or low-specific activity radioactive
vitamin D.
• The discovered vitamin D was the 1st active metabolite of vitamin D
isolated and identified and it is more potent than vitamin D3 since it
promotes intestinal Ca transport and treats rickets.
• Chemical synthesis of the compound and addition of tritium in the
molecule developed a more polar metabolite which was isolated in 1970
and its structure was identified as 1,25-(OH)2D3.

4. Introduction
• Synthesised primarily in the kidneys, 1,25-(OH)2D3 is the metabolically
active form of vitamin D involved in intestinal Ca transport, bone Ca
mobilisation and mineralisation of skeleton.
• In 1974, vitamin D endocrine system was detected through the deep
research of the manufacture of 1,25-(OH)2D3. Besides, studies showed
that a nuclear protein is the source of the vitamin D receptor (VDR).
• Isolation and investigations of VDR were performed by molecular cloning
and meanwhile other metabolites of vitamin D were found namely 24,25-
(OH)2D3 whose functions were vainly proved.
• Although several pathways of vitamin D have been now determined
regarding the degradation and elimination of vitamin D compounds,
other metabolism functions of vitamin D are still searched.

5. Enzymes involved in functional
metabolism pathway
• Since any additional functional pathways of vitamin D have yet been
discovered, the enzymes implicated in the activation of more polar
vitamin D are defined.
• According to experiments performed on mice, the cloned enzyme
CYP27B1 was indicated to be involved in the formation of 1,25-
(OH)2D3 in the kidneys or other autocrine or paracrine tissues.
• This enzyme helps vitamin D in metabolism of Ca and phosphorus
and skeleton and its activation is important in the treatment of rickets
and osteomalacia.
• However, the initial step of its activation is unclear as animal studies
have shown that only 75% of 1,25-(OH)2D3 is produced through
CYP27B1 enzyme. So, the remaining 25% is still unidentified.

6. Vitamin D receptor (VDR)
• VDR is located in many other tissues than in expected target tissues
responsible for:
– Calcium homeostasis
– Healing of rickets
– Osteomalacia
• Vit D functions beyond skeletal health and growth
• Selective anti-receptors have been defined that can yield many information
on tissue location.
– Exclude tissues with VDR previously studied
– Skeletal and heart muscles lack VDR
– VDR found in keratinocytes, lymphocytes, macrophages etc
• In vitro studies showed that VDR may have non-genomic-related functions.

7. Role of vitamin D in immune system
• Despite numerous studies, there is no association how VDR functions in
the immune system.
• Vit D deficiency and excess play important role in immunosuppression.
– Vit D deficiency delays hypersensitivity
– Vit D excess suppresses delayed hypersensitivity response
• Multiple sclerosis (MS)  1/Sunlight
– UV7-dehydrocholesterolprevitamin DVit D3
– Is UV or Vit D responsible for suppression of MS?
– Cantorna et al: Active Vit D suppressed Encephalomyelitis (EAE) but provoked
hypercalcemia (HC)
– Low doses of Vit D that do not produce HC, do not suppress EAE.
– Hypercalcemia not found when subject is exposed to UV

8. – Use of active Vit D cannot be used to treat MS or any autoimmune diseases.
– Cantorna et al: Animals given low calcium diet along with Vit D lost its ability to
suppress EAE until high doses (causing HC) were given
– Meehan et al: In females, HC itself could treat EAE but not MS while UV could treat
both without HC  UV can treat these conditions within a narrow wave band of light
(305-315nm) irrespective of Vit D
– Yang et al: In respect to hypersensitivity studies; showed that Vit D deficiency and
absence of VDR can suppress or reduce EAE in mice.
– Thus, autoimmune diseases need the presence of Vit D and VDR.
– Was it Vit D hormone or its precursor 25-hydroxy Vit D3?
– Exp: CYP2R1& CYP27B1 were knocked-out  could not prevent EAE
– This suggests either there is some other form of Vit D which has still not been identified
or Vit D-receptor interaction is required for development of EAE.
Role of vitamin D in immune system

9. Conclusion
• Vit D3 or an unknown metabolite is responsible for the development
of any component in the immune system.
– Development of EAE
– Any autoimmune diseases
• Vit D (poor ligand to VDR) & VDR are both required for EAE a
metabolite is required
• Since it’s not the known metabolites;
NOT ALL IS KNOWN ABOUT THE FUNCTIONAL METABOLISM
OF VITAMIN D

10. References
• DELUCA, H.F., 2014. Is there more to learn about functional vitamin
D metabolism? Journal of Steroid Biochemistry & Molecular Biology;
148(2015), 3-6.