Vitamin D

• Fat-soluble vitamin

• Sources – Foods

• Naturally found in very few foods• Added to many foods on the market

– Supplements– Sunlight

Vitamin D

• Daily Recommended Intake

– Current minimum intake recommendations

• Birth-50 years = 200 IU

• 51-70 years = 400 IU

• 71+ years = 600 IU

– Currently being debated

Food Sources of Vitamin D 3 oz smoked salmon = 583 IU

3 oz light tuna, canned in oil = 229 IU

1 large, whole egg = 29 IU

Foods Fortified with Vitamin D

8 oz skim milk = 115 IU

8 oz orange juice = 100 IU

1 cup Cheerios = 40 IU

½ cup yogurt = 40 IU

Definitions• 7-dehydrocholesterol: provitamin D3

• Previtamin D3: cholecalciferol

• Vitamin D3: produced in the skin from irradiated 7-DHC, isomerized previtamin D3

• Vitamin D2: from plants, from irradiated ergosterol

Vitamin D synthesis

• Vitamin D3 is hydroxylated in the liver:

25 OH vitamin D: inactive, measured in serum as the biomarker of vitamin D status from all sources

• Second hydroxylation:

1,25 (OH)2 vitamin D in the kidney

*** These hydroxylation steps can also occur in keratinocytes, prostate cells and others

Vitamin D3 can be obtained in diet, or derived from cholesterol in a reaction that requires UV light.

UV light

spontaneous

liver enzyme25-hydroxylase

Vitamin D3

calcitriol

Vitamin D binds to a “vitamin D binding protein” (VDP) for transport to target organs.

Vitamin D is not active itself (it’s a prohormone); it is modified to yield biologically active forms, such as calcitriol.

Calcitriol (derived from vitamin D) is a transcription factor, influencing expression of proteins involved in calcium absorption and transport.

Vitamin D is also important for immune system function.

Deficiency causes rickets, bone loss.

Calcitriol, from vitamin D.

Vitamin D production requires UV light (sunlight).

Sometime after humans migrated north out of Africa about 50,000 years ago, mutations appeared that reduced melanin (pigment) production in the skin, permitting vitamin D production with less sunlight.

Disadvantages of less melanin production are skin that is easily damaged by the sun, skin cancer risk, and loss of folic acid due to UV damage.

The melanin-reducing mutations helped early humans make vitamin D in northern europe in winter.

Vitamin D 25(OH)D 1,25(OH)DVitamin D 25(OH)D 1,25(OH)D 26

+ cells throughout the body

7-dehydrocholesterolUVB UVB

photonsphotons

Vitamin D Functions

• Many uses in the body– Promotes absorption of calcium from the small

intestine– Maintain blood levels of calcium and

phosphate for bone formation, mineralization, growth, and repair

– Improves muscle strength and immune function

– Reduces inflammation

Noncalcemic Functions of Noncalcemic Functions of 1,25-dihydroxyvitamin D1,25-dihydroxyvitamin D

CytokinesCytokines

Adaptive Innate Immune modulation

Vitamin D Deficiency

• At risk populations– Breastfed infants– Older adults– People with limited sun exposure– Darker skin pigments– Certain religious groups

Vitamin D Related Diseases

– Rickets– Osteomalacia– Osteoporosis

Vitamin D DeficiencyVitamin D Deficiency

Rickets, Osteomalacia

Influenza, Tuberculosis

MS, RA, SLE, Type I diabetes

Hypertension, CAD, PVD, CHF

Syndrome X, Type 2 Diabetes

Chronic Fatigue, SAD,

Depression

Cataracts, Infertility Osteoporosis

Cancer

System and Tissue Distribution of Nuclear System and Tissue Distribution of Nuclear

Vitamin D Receptors (VDR)Vitamin D Receptors (VDR) System Tissue

Immune Thymus, bone marrow, macrophages, B cells, T cells

Gastrointestinal Esophagus, stomach, small intestine, colon, rectum

Cardiovascular Endothelial cells, smooth muscle cells, myocytes

Respiratory Lung alveolar cells

Hepatic Liver parenchyma cells

Renal Proximal and distal tubules, collecting duct

Endocrine Parathyroid, thyroid, pancreatic beta cells

Exocrine Parotid gland, sebaceous gland

CNS Brain neurons, astrocytes, microglia

Epidermis/appendage Skin, breast, hair follicles

Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle

Connective Tissue Fibroblasts, stroma

Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac

Diverse Structure of Ligands for Nuclear Receptors

VDR+1

Gene Transcription

RNA Polymerase II

CYTOPLASM

NUCLEUS

VITAMIN D (V) RECEPTOR (VDR)ACTIVATION OF A VDR RESPONSIVE GENE

Hormone Regulated GeneVDRE

V

VDR

RXR

RXR VDR

V

V

V

NutrigenomicsNutrigenomics

Vitamin DVitamin D

Wood RJ, Tchack L, Angelo G, etal. DNA Microarray Analysis of Vitamin D-induced Gene Expression in a Human Colon Carcinoma Cell Line. Physiological Genomics 2004;17:122-129.

Confirmatory PCR for 1,25-dihydroxyvitamin D-regulated genes Confirmatory PCR for 1,25-dihydroxyvitamin D-regulated genes found by Affymetrix GeneChip transcriptional profilingfound by Affymetrix GeneChip transcriptional profiling

Vitamin D and Cancer

• Roles in prevention of– Colon cancer– Breast cancer

Human Migration Out of AfricaHuman Migration Out of Africa

3535° N° N

35° S35° S

Lamson Rl, etal. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 2005;310:1782-1786.

Vitamin D and Cancer

• How it prevents– Promotes cellular differentiation– Decreases cancer cell growth– Stimulates cell deaths

Vitamin D Cancer Research

• Mostly observational studies, only show correlation– Food frequency questionnaires– Interviews– Diet records

Vitamin D & Colon Cancer Research

• Third National Health and Nutrition Examination Survey– Epidemiologic study– 16,818 participants– Examined blood levels of vitamin D– Results

• Blood levels 80nmol/L or higher reduced risk by 72%

Vitamin D Cancer Research

• American Cancer Society’s Cancer Prevention Study II Nutrition Cohort– Studied 120,000 men and women– Analyzed diet, medical history, and lifestyle– Results

• Men with intakes of 520 IU or higher from both diet and supplementation slightly lowered risk

• No effect in women

Vitamin D & Breast Cancer Research

• Cancer Prevention Study II Nutrition Cohort– Participants

• 68,567 postmenopausal women

– Completed questionnaire on dietary intake, family history, and supplement use

– Results• Women who consumed higher amounts of vitamin D

and calcium from dairy products reduced their risk of breast cancer

Multiple Sclerosis Prevalence for U.S. WWII, KC Veterans at Time of Entery into the Armed Forces vs. Latitude

Latitude (degrees N)

25 30 35 40 45 50

20

40

60

80

100

120

140

160

180

200

220

Multiple Sclerosis in World War II Multiple Sclerosis in World War II Veterans by Latitude and State of Veterans by Latitude and State of

ResidenceResidence

Wallin MT, etal. Multiple sclerosis in US veterans… Ann Neurol 2004;55:65-71

Tuberculosis Treated with Sunshine Tuberculosis Treated with Sunshine

Preop Vitamin D3 levels Preop Vitamin D3 levels in 73 Veterans Undergoing Heart in 73 Veterans Undergoing Heart Surgery at the Seattle VA HospitalSurgery at the Seattle VA Hospital

No. of

Patients

History of Cancer

25-hydroxyvitamin D3

Level (ng/ml) 7 (9.6 %) 1 (colon) < 8 (severely

deficient)

41 (56.2%)

6* 8-19.9 (deficient)

9 (12.3%) 0 20-29.9 (insufficient)

13 (17.8%)

0 30-49.9 (sufficient)

3 (4.1%) 0 50-100 (optimal)

* Prostrate cancer – 3; Colon cancer – 1; Tonsillar cancer – 1; Melanoma -- 1

Surgery performed December 2006 – July 2007Surgery performed December 2006 – July 2007

Benefits of Vitamin DBenefits of Vitamin D• Skeletal-muscularSkeletal-muscular

– Strong muscles and bonesStrong muscles and bones• InfectionsInfections

– Prevent influenza, treat tuberculosisPrevent influenza, treat tuberculosis• CancerCancer

– Prevent breast, colon, and prostate cancerPrevent breast, colon, and prostate cancer– ? Suppress metastasizes ? Suppress metastasizes

• Autoimmune DiseasesAutoimmune Diseases– Prevent multiple sclerosis and type 1 diabetesPrevent multiple sclerosis and type 1 diabetes

• Cardiovascular DiseaseCardiovascular Disease– Slow progression of atherosclerosisSlow progression of atherosclerosis– Treat hypertension and congestive heart failureTreat hypertension and congestive heart failure

• Neuropsychiatric DisordersNeuropsychiatric Disorders– Prevent schizophrenia and relieve depressionPrevent schizophrenia and relieve depression