vitamin d synthesis and photocarcinogenesis what’s the right balance for sun exposure?
TRANSCRIPT
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Vitamin D synthesis and photocarcinogenesis
What’s the right balance for sun exposure?
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Ultraviolet radiation is a carcinogen
• Sun exposure is the major environmental cause of skin cancer
• BCC, SCC• Melanoma
International Agency for Research on Cancer, 1992National Toxicology Program, Report on Carcinogens, 2000, 2002
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0 10000 20000 30000 40000 50000 60000 70000 80000 90000
Non-Hodgkin'sLymphoma
Colorectum
Prostate
Breast
Lung
Skin
Number of new cases, Canada, 2005
> 80,000 Canadians were diagnosed with skin cancer in 2005 - 1/3 of new cancers
Source: Canadian Cancer Statistics 2005
Skin cancer is common
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0
2
4
6
8
10
12
14
16
1971 1976 1981 1986 1991 1996 2001Year of diagnosis/death
Ag
e-st
and
ard
ized
rat
e p
er10
0,00
0
Male incidence Female incidence
Male mortality Female mortality
Source: Cancer Care Ontario (Ontario Cancer Registry, 2004). 3-year moving averages standardized to the Canadian 1991 population.
Melanoma incidence and mortality, Ontario, 1971-2002
…and is becoming more commonMelanoma incidence and mortality rates have risen 2-3 fold in 30 years
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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
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UV: DNA damage
• Cyclobutane pyrimidine dimers :
signature mutation
• 6-4 pyrimidine pyrimidone photoproducts
• Single strand breaks
• DNA protein crosslinks
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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
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UV induces an alteration in immune surveillance
• Decreased ability to eliminate cancerous growths
• Interference with development of contact hypersensitivity
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Public health message: sun protection/skin cancer prevention
• Shade
• Clothing
• Education
• Public policy
• Sunscreen use
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Vitamin D
• Definitions
• Vitamin D: UVB induced production in the skin
• Vitamin D and bones
• Vitamin D and other disorders
• Public health message
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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
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Vitamin D synthesis
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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
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1,25 (OH)2 vitamin D
• Serum levels are tightly regulated
• Do not vary by latitude
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Sources of vitamin D
• Sunlight (UVB)
• Food (vitamin D3 and vitamin D2)
• Fortification of foods: milk, orange juice
• Dietary supplements
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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
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Function of vitamin D
• Increases calcium absorption from the gut
• Calcium homeostasis
• Maintenance of bone mineral density
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Vitamin D deficiency
• Rickets
• Osteomalacia
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Vitamin D insufficiency25-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 700-800 IU/day, higher than currently recommended doses
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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
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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
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Vitamin D supplementation
• Prevention of fractures in the elderly
• Prevention of falls in the elderly
• Prevention of periodontal disease in the elderly
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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
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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
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Epidemiologic studies
Less evidence exists for a role for sunlight in:
• Multiple sclerosis
• Diabetes
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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
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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
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What to do?
• Many advocate for taking vitamin D supplements
• Advocate for increased fortification of foods where it is not in place
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What to do?
1. Many people do not avoid the sun, and produce adequate vitamin D in the skin depending on the time of year.
2. Incidental sun exposure throughout the year likely produces adequate vitamin D in the skin for many people
3. Vitamin D supplementation for those at increased risk
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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
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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, 1995Wolpowitz D et al. J Amer Acad Dermatol 54:301,
2006
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