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 enzyme
25-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)D
26
+ cells throughout
the body
7-dehydrocholesterol
UVB
photons
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
1,25-dihydroxyvitamin D
Cytokines
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 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
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
VIT AMIN D (V) RECEPTOR (VDR)
ACT IVAT ION OF A VDR RESPONSIVE GENE
RNA Polymerase II
VDRE
Hormone Regulated Gene
+1
RXR VDR
V
NUCLEUS
Gene
T ranscription
RXR VDR
V
VDR
CYT OPLASM
V
V
Nutrigenomics
Vitamin D
Confirmatory PCR for 1,25-dihydroxyvitamin D-regulated genes found
by Affymetrix GeneChip transcriptional profiling
Wood RJ, Tchack L, Angelo G, etal. DNA Microarray Analysis of Vitamin Dinduced Gene Expression in a Human Colon Carcinoma Cell Line.
Physiological Genomics 2004;17:122-129.
Vitamin D and Cancer
• Roles in prevention of
– Colon cancer
– Breast cancer
Human Migration Out of Africa
35° N
35° 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 in World War II
Veterans by Latitude and State of
Residence
Multiple Sclerosis Prevalence for U.S. WWII, KC Veterans
at Time of Entery into the Armed Forces vs. Latitude
220
MS Prevalence (relative units)
200
180
160
140
120
100
80
60
40
20
25
30
35
40
45
50
Latitude (degrees N)
Wallin MT, etal. Multiple sclerosis in US veterans… Ann Neurol 2004;55:65-71
Tuberculosis Treated with Sunshine
Preop Vitamin D3 levels
in 73 Veterans Undergoing Heart
Surgery at the Seattle VA Hospital
No. of
Patients
7 (9.6 %)
41
(56.2%)
9 (12.3%)
History of 25-hydroxyvitamin D3
Cancer
Level (ng/ml)
1 (colon)
6*
0
< 8 (severely
deficient)
8-19.9 (deficient)
20-29.9 (insufficient)
0
30-49.9 (sufficient)
13
* Prostrate cancer – 3; Colon cancer – 1; Tonsillar cancer – 1; Melanoma -- 1
(17.8%)
Surgery
performed
2006 –(optimal)
July 2007
0 December50-100
3 (4.1%)
Benefits of Vitamin D
• Skeletal-muscular
– Strong muscles and bones
• Infections
– Prevent influenza, treat tuberculosis
• Cancer
– Prevent breast, colon, and prostate cancer
– ? Suppress metastasizes
• Autoimmune Diseases
– Prevent multiple sclerosis and type 1 diabetes
• Cardiovascular Disease
– Slow progression of atherosclerosis
– Treat hypertension and congestive heart failure
• Neuropsychiatric Disorders
– Prevent schizophrenia and relieve depression