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, 1992National Toxicology Program, Report on Carcinogens, 2000, 2002

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

0

2

4

6

8

10

12

14

16

1971 1976 1981 1986 1991 1996 2001Year of diagnosis/death

Ag

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and

ard

ized

rat

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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

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

• Shade

• Clothing

• Education

• Public policy

• Sunscreen use

Vitamin D

• 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

• 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 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

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

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, 1995Wolpowitz D et al. J Amer Acad Dermatol 54:301,

2006