The Sunshine Vitamin in Health and Disease

© BioSoft Publishing 2009

Oh, thou life giving celestial body, welcome to the new day – Anonymous

UV rays and their biological action on skin cells

UVB causes sunburns (longer exposure)

UVA produces tanning without burning. Longer exposure causes sunburns.

The mechanism of sunburns

Sunburns take place in several steps:

1. Initial redness and swelling – dilation of blood capillaries in the dermis

2. An inflammatory response is triggered – synthesis of cytokines, prostaglandins, heat shock proteins

3. Inflammatory cells (lymphocytes, macrophages) move to the interstitial space. Dark red skin, heat and pain sensation

4. After 72 hours massive skin peeling off takes place.

An overexposure to UV radiation (typical summer day) can cause sunburn and in the long run some form of skin cancer.

The most deadly form – malignant melanoma is mostly caused by indirect DNA damage, through oxidative stress due to reactive oxygen species.

Damage to DNA strands caused by UVB radiation

UVB can damage DNA directly by causing the formation of a cyclobutane thymine dimer involving two adjacent thymine bases. A bulge appears in one of the strands and as a result DNA replication is impaired.

Site of vitamin D synthesis in the skin

UVB radiation causes the photo-isomerization of 7-dehydrocholesterol in the plasma membrane of stratum spinosum and stratum basale cells of the epidermal layer of the skin. UVB rays are most effective in a narrow range, between 295-300 nm. Generation of pre-vitamin D3 depends on the intensity and wavelength of UV radiation. Under normal circumstances some 25-50 micrograms of 7-dehydrocholesterol/cm2 of skin are available for vitamin D3 synthesis.

Following a moderate exposure to sunlight UVB rays trigger the synthesis of melanin by the melanocytes in the lower strata of epidermis. The pigment can be a limiting factor in the photo-

isomerization reaction because melanin can also absorb UVB radiation.

Synthesis of1, 25(OH)2 vitamin D3

It has been shown recently that human macrophages treated with a mycobacterium lipoprotein showed increased expression of 25OH D-1alpha hydroxylase and vitamin D receptor as well as the induction of cathelicidin (a class of antimicrobial peptides called defensins) in response to 25(OH) vitamin D3 .

Generation of vitamin D3 and its involvement in calcium metabolism

Biological functions of vitamin D3

Well known for a long time:

Regulation of calcium absorption in the gut

Regulation of calcium uptake by the bone tissue

Regulation of calcium metabolism in muscle

Recently added to the list:

Role in cancer prevention

Role in the regulation of immune function and autoimmune disorder prevention

Role in hypertension and CVD prevention

Role in the regulation of insulin production

Possible involvement in the modulation of cognitive function

Vitamin D deficiency (hypovitaminosis) can be caused by:

Inadequate intake from foods coupled with inadequate sunlight (UVB) exposure

Disorders that limit its absorption such as Crohn’ disease, cystic fibrosis and Sprue

Liver or kidney disorders that impair the conversion of cholecalciferol to its biologically active 1,25(OH)2 vitamin D3

Aging, increased skin pigmentation and obesity

Vitamin D deficiency has been linked to:

Increased susceptibility to high blood pressure and arteriosclerosis

Autoimmune disorders including type 1 diabetes

Cancer

Periodontal disease

Multiple sclerosis

Chronic pain

Depression

Poor physical performance in older adults and cognitive impairment

Behavioral dysfunction (there is some evidence pointing to an association of schizophrenia with winter births and higher latitude).

Vitamin D and cancer

Regulation of prostate cell growth by 1,25(OH)2 D3

By binding to its nuclear receptor (VDR) vitamin D3 alters the gene expression that regulates cell-cycle arrest, apoptosis and differentiation. Augmented levels of circulating 25(OH)D3 lead to increased synthesis of 1,25()H)2 D3 in extrarenal cells and that helps control growth and maturation, thus decreasing the risk of malignancy. It appears that a 25(OH)D3 blood plasma concentration of at least 20 ng /ml may reduce the risk of developing colon, prostate and breast cancer by 30 to 50%.

The interplay between the enzymes that synthesize and inactivate 1,25(OH)2D3 , respectively

Modulation of prostaglandin gene expression by vitamin D3

Effect of nutrients on vitamin D metabolism

Low serum Ca2+ concentration stimulates renal synthesis of 1,25(OH)2 D3 synthesis

Soy genistein inhibits CYP 24 activity

Dietary folate inhibits CYP 24 activity by increasing methylation status of the promoter region and by down-regulating expression of the gene for this enzyme

Vitamin D receptor (VDR) and diet in relation to cancer risk

Vitamin D receptor gene expression is crucial to vitamin D anticancer activity.

Experimental animals that lack VDR have shown increased number of chemically-induced tumors in mammary, skin, prostate and colon organ but not in ovary, liver, lung and uterus organs.

Rodents (that usually do not develop colon cancer) fed a diet high in saturated fats and phosphorus and low in calcium, fiber, choline, methionine, folate and vitamin D develop spontaneous colon cancer in some 25% of the cases.

Future research trends related to vitamin D and cancer

There is a clear need to:

Develop predictive, validated and sensitive biomarkers to evaluate intake or exposure to vitamin D that also includes measuring dietary and supplemental vitamin D intake. At present, the most used biomarker of vitamin D status is 25(OH) D3 but there are no standardized methods for the assay of this metabolite.

Better understanding of susceptibility biomarkers where polymorphism plays a major role.

polymorphism in VDR was linked to cancer risk.

relationship between polymorphisms in other genes in the vitamin D metabolic pathway such as CYP 24 and CYP 27B1, vitamin D status and cancer risk.

Better understanding of molecular targets for vitamin D.

Vitamin D and the immune function

Background

Research carried out in the 1980s and 1990s has indicated that:

Elevated serum levels of 1,25(OH)2 D3 are frequently recorded in sarcoidosis patients where the disease-associated macrophages expressed CYP 24B1 activity.

1,25(OH)2 D3 inhibited the proliferation of cells expressing the VDR.

Vitamin D and innate immunity

Key points:

Screening the human genome for potential vitamin D target genes revealed a 1,25(OH)2 D3 response element in the promoter gene for cathelicidin (antimicrobial peptide called defensin) expressed in cells such as epithelial cells, keratinocytes and some myeloid cell lines.

Cathelicidin was also induced by 25(OH)D in cells that express the CYP 27B1.

1,25(OH)2 D3 can induce other factors associated with bacterial killing, e.g. NO synthase.

Vitamin D mediated immune response has two important benefits for the host:

1. Macrophage-generated 1,25(OH)2 D3 supports local immunity by enhancing the expression of defensins. Some bacterial species ‘fight back’ by inhibiting the expression of defensins.

2. 1,25(OH)2 D3 also downregulates expression of pathogen recognition receptors and in so doing it acts to limit inflammatory T lymphocyte responses that would otherwise promote autoimmunity mediated by T helper1 lymphocytes.

25(OH) D3 and innate immunity

Important points to remember: Immune responses involve local metabolism of vitamin D as shown by the way 25(OH) D3 influences innate immunity.

The presence of VDR in human activated T & B lymphocytes provided evidence for the involvement of vitamin D in processes other than calcium homeostasis and indicated a functional role for this vitamin as a mediator of the acquired (adaptive) immunity.

1,25(OH)2 D3 was found to exert direct effects on B lymphocyte homeostasis by inhibiting its differentiation to plasma cells and class-switched memory cells. This finding suggested a possible role for vitamin D in B lymphocyte-related disorders such as systemic lupus erythematosus.

Tissue specific synthesis of 1,25(OH)2 D3 from 25(OH) D3 is crucial to both adaptive and innate immune systems.

Vitamin D deficiency is associated with compromised immunity, which means an increased risk for infectious diseases such as tuberculosis and an increased susceptibility to type 1 diabetes.

Vitamin D and the cognitive function

There has been growing evidence in the past 20 years or so that micronutrient inadequacy may adversely affect brain function. If a causal relationship between micronutrient deficiencies and the underperforming brain could be demonstrated, that would have major public health implications in terms of enormous savings in medical treatment and care. In the next few slides some of the evidence suggesting such a causal relationship with regard to vitamin D involvement in brain development and cognitive/behavioral function will be presented.

1,25(OH)2 D3 target genes in the brain*

Pro-inflammatory cytokine-induced cognitive/behavioral dysfunction and the possible role of vitamin D3 (calcitriol)

There is ample evidence to support the notion that depression is associated with increased concentrations of inflammatory cytokines.

Calcitriol modulates the enhanced cellular immune response pathway (Th 1) and autoimmune response. The regulatory mechanism involves the decrease of production of pro-inflammatory cytokines and the increase in the synthesis of anti-inflammatory cytokines. This effect was observed in monocytes, microglia, keratinocytes, endothelial cells and human benign prostate hyperplastic cells.

Although there is a large body of evidence showing that poor 25(OH) D3 status is clearly associated with many human diseases in which depression is also a factor, the possible involvement of calcitriol in depression-associated diseases has only been suggested in anxiety and depression fibromyalgia subjects.

Key points:

Evidence that calcitriol is involved in both brain development and function is very strong.

Evidence regarding the effect of calcitriol on cognitive/behavioral brain functions is rather suggestive and not so clear-cut.

Studies in humans and rodents that directly examined effects of vitamin D deficiency or supplementation on cognitive/behavioral performance suggest subtle changes of those brain functions and several other factors besides vitamin D may come into play. Also, the evidence base does not appear to be solid enough to indicate that there is a direct causal relationship.

Relationship between vitamin D, pro-inflammatory cytokines and cognitive dysfunction

Checking the vitamin D status

The best indication of one’s vitamin D status is the blood level of 1,25(OH)2 D3 . The precursor to calcitriol is a better marker of overall vitamin D status than calcitriol itself.

Sun exposure is the best way to get vitamin D synthesized in the skin. It is important to get the optimal sun exposure as opposed to lots of sun exposure. Enough exposure is considered when the skin turns slightly pink. Beyond that is sunburn and skin damage.

When using oral vitamin D supplementation it is recommended to check with a health care professional.

Good nutrition enhances the quality of life and helps you prevent disease.

The best source of quality micronutrients is in fresh fruit and vegetables. Don’t forget: five servings per day!

Credits:

sunburn-UV.jpg: http://www.rd.com/advice-and-know-how/how-sunburn-works/article76374.html

Badger-spf-30-chart.gif: http://earthturns.com/ProductDetails.asp?ProductCode=B-SPF30_TUBE

uvin.jpg: http://coolshade.tamu.edu/burn1.htm

UV_SkinLayer.jpg: http://www.skinstore.com/store/category.asp?catID=7368

250px-skinlayers.jpg: http://en.wikipedia.org/wiki/Vitamin_D

SOD enzyme on music: http://whozoo.org/mac/Music/index.htm (Dr. M.A. Clark, Texas Wesleyan University)

DNA_UV_mutation.jpg http://en.wikipedia.org/wiki/Ultraviolet

VitD&Prostate Cell: Reproduced from J.Nutr. 135, 2739S-2748S (2005)

25(OH)D3&innate immunity: Reproduced from Nat.Clin.Pract.Endocrinol.Metab. 4(2) 80-90 (2008)

VitD&Cognitive Function: Reproduced from FASEB Journal 22, 982-1001 (2008)

DNA and proteins can “sing” and that’s part of the metabolic symphony that cells play nonstop. As you can hear there is harmony in the melody that super-oxide dismutase is singing!

For the inquisitive mind:

An exciting and provocative book by Bruce Lipton (The Biology of Belief – Hay House, 2008) will certainly challenge the way we look at ourselves and the world around us. Dr. Lipton discusses The Four Myth perceptions of the Apocalypse on YouTube:

http://www.youtube.com/watch?v=VRDHBA8w1f0&feature=PlayList&p=CEB7B6B207992634&playnext=1&playnext_from=PL&index=4The four myth perceptions, according to Dr. Lipton are:

You live in a mechanical universe

Your genes control your life

Life is based on survival of the fittest

Life evolved as a random process