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Vitamin D synthesis and photocarcinogenesis

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Presentation on theme: "Vitamin D synthesis and photocarcinogenesis"— Presentation transcript:

1 Vitamin D synthesis and photocarcinogenesis
What’s the right balance for sun exposure?

2 Ultraviolet radiation is a carcinogen
Sun exposure is the major environmental cause of skin cancer BCC, SCC Melanoma International Agency for Research on Cancer, 1992 National Toxicology Program, Report on Carcinogens, 2000, 2002

3 Skin cancer is common > 80,000 Canadians were diagnosed with
skin cancer in /3 of new cancers Source: Canadian Cancer Statistics 2005

4 …and is becoming more common
Melanoma incidence and mortality rates have risen 2-3 fold in 30 years Melanoma incidence and mortality, Ontario, Source: Cancer Care Ontario (Ontario Cancer Registry, 2004). 3-year moving averages standardized to the Canadian 1991 population.

5 Ambient UV, type and amount of exposure and susceptibility determine risk
Skin cancer risk is higher in susceptible populations living closer to the equator The higher the total lifetime amount of UV exposure, the greater the risk of skin cancer An intermittent pattern of intense exposure appears to increase the risk of melanoma People with sun-sensitive skin (i.e., burn easily, tan poorly), blue eyes, many nevi are at greater risk of developing skin cancer

6 UV: DNA damage Cyclobutane pyrimidine dimers : signature mutation
6-4 pyrimidine pyrimidone photoproducts Single strand breaks DNA protein crosslinks

7 UV: membrane damage Lipid peroxidation
Activation of surface receptors with induction of multiple signal transduction pathways: alteration in activation of many cellular proteins……alteration in gene expression and cellular function

8 UV induces an alteration in immune surveillance
Decreased ability to eliminate cancerous growths Interference with development of contact hypersensitivity

9 Public health message: sun protection/skin cancer prevention
Shade Clothing Education Public policy Sunscreen use

10 Vitamin D Definitions Vitamin D: UVB induced production in the skin
Vitamin D and bones Vitamin D and other disorders Public health message

11 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

12 Vitamin D synthesis

13 Definitions 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

14 1,25 (OH)2 vitamin D Serum levels are tightly regulated
Do not vary by latitude

15 Sources of vitamin D Sunlight (UVB) Food (vitamin D3 and vitamin D2)
Fortification of foods: milk, orange juice Dietary supplements

16 Action spectra UVB is the waveband required for vitamin D synthesis
The action spectra for sunburn, cyclobutane pyridine dimers all peak in the UVB range With longer UVB exposure, vitamin D synthesis does not continue, but DNA damage does

17 Function of vitamin D Increases calcium absorption from the gut
Calcium homeostasis Maintenance of bone mineral density

18 Vitamin D deficiency Rickets Osteomalacia

19 Vitamin D insufficiency 25-OH vitamin D level
Optimal concentration remains undecided In a meta-analysis of fracture prevention in the elderly, showed that fracture prevention was greatest when 25-OH vitamin D levels were ~100 nmol/L: these studies used oral supplementation This required vitamin D intakes of IU/day, higher than currently recommended doses

20 People at risk for low 25-OH vitamin D
Elderly Northern latitudes in winter Black skin (melanin) Cultural or lifestyle choices Sun avoiders, post-organ transplant

21 2005 Dietary Guidelines for Americans
Individuals at high risk (older adults, people with dark skin, those with little sunlight exposure) should consume extra vitamin D from fortified foods or supplements Recommendation of 25ug (1000 IU) vitamin D daily to maintain adequate 25-OH vitamin D Do not use UV exposure to obtain additional vitamin D Johnson MA et al. Nutr Rev 64:410,2006

22 Vitamin D supplementation
Prevention of fractures in the elderly Prevention of falls in the elderly Prevention of periodontal disease in the elderly

23 Colorectal neoplasia Epidemiologic data are generally consistent with a protective effect of a higher 25(OH)D concentration and higher vitamin D intake The biologic basis for the sensitivity of “digestive malignancies” to vitamin D status is unclear” Randomized control studies are needed Bischoff-Ferrari H et al. Am J Clin Nutr 84:18, 2006 Giovannucci E. Cancer Epidemiol Biomarkers Prev 15:2467, 2006

24 Prostate and breast cancer
Studies have shown geographic gradients in risk. Case control studies and cohort studies have shown a decreased risk of these diseases with increased sunlight exposure Hypothesis generating: Is it the vitamin D that is protective? The potential for cancer prevention by oral intake of vitamin D must be tested in clinical trials van der Rhee HJ et al Eur J Cancer 42:2222, 2006 Gallagher RP et al. Lancet Oncology 6:634, 2005

25 Epidemiologic studies
Less evidence exists for a role for sunlight in: Multiple sclerosis Diabetes

26 Life is not so simple Vitamin D is important for bone health
There is some data supporting vitamin D as protective against certain diseases Agreement on appropriate levels of 25-OH vitamin D have not been established Sunlight, a source of vitamin D, is a carcinogen

27 What to do? Some advocate for increased unprotected UV exposure
This advice is complex: latitude, weather dependent, time of day and season. It will not be effective in higher latitudes during the winter It is inefficient in the elderly, blacks Many people (such as teenagers, many adults) already are exposed to enough unprotected UV exposure that more UV exposure will not be helpful

28 What to do? Many advocate for taking vitamin D supplements
Advocate for increased fortification of foods where it is not in place

29 What to do? Many people do not avoid the sun, and produce adequate vitamin D in the skin depending on the time of year. Incidental sun exposure throughout the year likely produces adequate vitamin D in the skin for many people Vitamin D supplementation for those at increased risk

30 What to do? Further research on the role of sunlight and vitamin D in cancer prevention Randomized controlled trials of dietary vitamin D as a cancer prevention agent

31 Sun protection messages
Remains important Prevention of skin cancer and photoaging Protection using hats, clothing, shade and sunscreen during leisure time/occupational exposure Standard use of sunscreens has not caused vitamin D deficiency Marks R et al. Arch Dermatol 131:415, 1995 Wolpowitz D et al. J Amer Acad Dermatol 54:301, 2006


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