Transcript DISCLOSURE OF CONFLICTS OF INTEREST

Vitamin D synthesis and
photocarcinogenesis
What’s the right balance for sun
exposure?
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
Skin cancer is common
> 80,000 Canadians were diagnosed with
skin cancer in 2005 - 1/3 of new cancers
Skin
Lung
Breast
Prostate
Colorectum
Non-Hodgkin's
Lymphoma
0
10000 20000 30000 40000 50000 60000 70000 80000 90000
Number of new cases, Canada, 2005
Source: Canadian Cancer Statistics 2005
…and is becoming more common
Melanoma incidence and mortality rates have risen 2-3 fold in 30 years
Age-standardized rate per100,000
16
14
Male incidence
Female incidence
Male mortality
Female mortality
12
10
8
6
4
2
0
1971
1976
1981
1986
1991
1996
2001
Year of diagnosis/death
Melanoma incidence and mortality, Ontario, 1971-2002
Source: Cancer Care Ontario (Ontario Cancer Registry, 2004).
3-year moving averages standardized to the Canadian 1991 population.
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
UV: DNA damage
• Cyclobutane pyrimidine dimers :
signature mutation
• 6-4 pyrimidine pyrimidone photoproducts
• Single strand breaks
• DNA protein crosslinks
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
UV induces an alteration in immune
surveillance
• Decreased ability to eliminate cancerous
growths
• Interference with development of contact
hypersensitivity
Public health message: sun
protection/skin cancer prevention
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Shade
Clothing
Education
Public policy
Sunscreen use
Vitamin D
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Definitions
Vitamin D: UVB induced production in the skin
Vitamin D and bones
Vitamin D and other disorders
• Public health message
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
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
1,25 (OH)2 vitamin D
• Serum levels are tightly regulated
• Do not vary by latitude
Sources of vitamin D
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Sunlight (UVB)
Food (vitamin D3 and vitamin D2)
Fortification of foods: milk, orange juice
Dietary supplements
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
Function of vitamin D
• Increases calcium absorption from the gut
• Calcium homeostasis
• Maintenance of bone mineral density
Vitamin D deficiency
• Rickets
• Osteomalacia
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 700-800
IU/day, higher than currently
recommended doses
People at risk for low 25-OH vitamin D
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Elderly
Northern latitudes in winter
Black skin (melanin)
Cultural or lifestyle choices
Sun avoiders, post-organ transplant
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
Vitamin D supplementation
• Prevention of fractures in the elderly
• Prevention of falls in the elderly
• Prevention of periodontal disease in the
elderly
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
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
Epidemiologic studies
Less evidence exists for a role for sunlight in:
• Multiple sclerosis
• Diabetes
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
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
What to do?
• Many advocate for taking vitamin D
supplements
• Advocate for increased fortification of
foods where it is not in place
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
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
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