Vitamin A and Skin Cancer and Ageing Skin

Why is vitamin A important for skin cancer protection?

The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body’s first line of defense against infection. Retinol (vitamin A) and its metabolites (e.g. beta carotene which is converted to vitamin A) are required to maintain the integrity and function of these cells.

McCullough, F. et al. The effect of vitamin A on epithelial integrity. Proceedings of the Nutrition Society. 1999; volume 58: pages 289-293

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In 1999 Researchers from the University of Michigan reported that ultraviolet irradiation from the sun causes a major loss of retinoic acid receptors in skin cells. They concluded that ultraviolet irradiation causes a vitamin A deficiency that may have harmful effects on skin function, contributing to premature aging of the skin and the creation of skin cancer.

Wang Z et al. “Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment.” Nature Medicine 1999; 5(4): 418-422

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A study conducted in 1992 at the University of Melbourne, Australia, involving 88 males consecutively admitted for the surgical removal of a basal cell carcinoma and squamous cell carcinoma, and of 88 male patients without skin cancers (controls) admitted for small elective surgical procedures.

All subjects were questioned about previous diet, alcohol consumption, and smoking habits and blood levels of beta-carotene and vitamin A were measured. Patients with skin cancers had a lower average blood level of beta-carotene and vitamin A than the patients without skin cancers.

Kune GA, Bannerman S, Field B, Watson LF, Cleland H, Merenstein D, Vitetta L. Diet, alcohol, smoking, serum beta-carotene, and vitamin A in male nonmelanocytic skin cancer patients and controls. Nutr Cancer. 1992;18(3):237-44.

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In 2001 researchers from The University of Texas, Baylor College of Medicine and the University of Arizona looked at the effects of sun exposure and retinoic acid (vitamin A) receptors in skin cells.

The study examined these effects in relation to squamous skin carcinogenesis (SCC) (the process by which normal cells are transformed into cancer cells).

They observed a progressive decrease in retinoic acid (vitamin A) receptors from normal skin to precancerous skin progressing to invasive skin SCC (squamous cell carcinogenesis).

Their results indicate that the suppression of retinoid (vitamin A) receptors occurs early in the precancerous stage and is associated with progression of squamous skin carcinogenesis (the creation of cancer).

Xu X-C, Wong WY, Goldberg L, et al. “Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis.” Cancer Res, 61: 4306-10, 2001.

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“The protective metabolite (substance involved in metabolism) of vitamin A is called retinoic acid. When we take vitamin A, our body naturally metabolizes some of it into retinoic acid. If levels of vitamin A are sufficient, more retinoic acid can be formed, which appears to protect retinoic acid receptors, and much of the “sun damage” is prevented. Skin cells can repair themselves better with sufficient retinoic acid, which is only possible with sufficient vitamin A”. (Jonathan Wright, M.D. Nutrition and Healing Newsletter, 06/02).

In 2001 a researcher from Switzerland noted in a lecture published in The Journal of Dermatology, that the Human epidermis (the outer layer of skin) contains significant amounts of Vitamin A, together with a complex system which controls (among other things) its metabolism toward either storage or activation.

In relation to this the researcher said, “This complex system may be drastically altered upon ultraviolet light exposure because vitamin A absorbs in the UVB range.”

This researcher and colleagues had conducted a series of experiments to analyze the effects of ultraviolet (UV) exposure on the epidermal (outer layer of the skin) stores of vitamin A.

He went on to say, “Current data indicate that the vitamin A system is a direct target of both UVB and UVA and participates in an adaptive response to UV exposure.” (Vitamin A adapts to protect the skin from any ultraviolet light damage, thereby resulting in the depletion of vitamin A through this protective activity).

The researcher concluded: “Interfering with this UV-induced vitamin A deficiency is a new concept for the prevention of skin cancer and aging.”

Saurat JH. Skin, sun, and vitamin A: from aging to cancer. J Dermatol. 2001 Nov;28(11):595-8.

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Swedish researchers, reporting in the journal Experimental Dermatology in 2003, used cultured normal human keratinocytes and melanocytes (skin cells) to examine the effects of UV irradiation on the main retinoid receptors in the human skin.

The keratinocyte is the major cell type of the epidermis (outer layer of skin), making up about 90% of epidermal cells. Melanocytes are cells located in the bottom layer of the skin’s epidermis.

The authors concluded that a depletion of vitamin A and retinoid receptors, together with other factors, by ultraviolet (UV) irradiation might seriously interfere with retinoid (vitamin A) signalling and therefore promote future tumour development, especially in keratinocytes (see above).

Andersson E, Rosdahl I, Torma H, Vahlquist A. Differential effects of UV irradiation on nuclear retinoid receptor levels in cultured keratinocytes and melanocytes. Exp Dermatol. 2003 Oct;12(5):563-71.

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In 1997 researchers at the University of Texas M. D. Anderson Cancer Center conducted a large trial with 2,297 participants with evidence of moderate to severe actinic keratosis and a history of more than 10 actinic keratoses and at most 2 squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) skin cancers.

(Actinic keratosis is a precancerous condition of thick, scaly patches of skin occurring on the sun-exposed skin of the face or hands, especially light-skinned people).

The trial, published in the journal Cancer Epidemiology Biomarkers & Prevention, tested the oral administration of 25,000 IU per day of vitamin A against a placebo (sugar pill) on the development of a first new skin cancer.

During an average follow-up time of 3.8 years, they found that 526 subjects had a first new skin cancer.

Comparing the vitamin A supplemented group with the placebo group they observed a 32 % risk reduction for squamous cell skin cancers.

The authors concluded that daily supplementation with 25,000 IU of retinol (vitamin A) was effective in preventing squamous cell carcinoma (SCC), although it did not prevent basal cell carcinoma (BCC).

Moon T, Levine N, Cartmel B, et al. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Cancer Epidemiol Biomarkers Prev 1997;6:949–56.

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Squamous cells are one of the three main types of cells in the epidermis, the top, outer layer of the skin.

The second most common type of non-melanoma skin cancer is squamous cell carcinoma. Although this type of cancer is more likely to metastasize (spread to lymph nodes or other sites in the body) than basal cell carcinoma, metastasis is still rare. Squamous cell carcinomas most commonly develop on sun-exposed parts of the skin, but can develop on other parts of the skin as well. (CancerConsultants.com).

In 2004 Researchers from the University of Arizona and the University of Texas M. D. Anderson Cancer Center who had previously established that 25000 IU per day of vitamin A resulted in a 32% risk reduction squamous cell skin cancers with virtually no toxic effects hypothesized that a vitamin A dose escalation to 50000 or 75000 IU per day would be both safe and more effective in skin cancer prevention.

129 participants with severely sun-damaged skin on their lateral forearms were randomly given either a placebo or oral retinyl palmitate (a common vitamin A supplement) 25,000, 50,000, or 75,000 IU per day for 12 months.

The researchers, reporting in the journal Clinical Cancer Research, noted that vitamin A doses could be increased safely to 50,000 and 75,000 IU per day for the 1 year period with no evidence of differences in the rate of vitamin A-related toxicities in comparison with either placebo (sugar pill) or 25,000 IU per day.

They noted a highly significant reduction of lateral forearm epidermal cell sun damage associated with the 50,000 and 75,000 IU per day vitamin A doses.

Their conclusion: “The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.”

Alberts D, Ranger-Moore J, et al. “Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin.” Clin Cancer Res. 2004 Mar 15;10(6):1875-80. Erratum in: Clin Cancer Res. 2004 Aug 15;10(16):5640.

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See further below about beta-carotene increasing lung cancer incidence.

Other factors also cause vitamin A depletion

In 1991 researchers T.E. Edes and colleagues reporting in the journal Nutrition and Cancer hypothesized that depletion of vitamin A can be induced by exposure to carcinogens (cancer causing substances) such as benzopyrene found in cigarette smoke.

The study was designed to determine if benzopyrene exposure depletes tissue vitamin A and whether beta-carotene might prevent the depletion. Rats were fed a diet containing benzopyrene supplemented with or without beta-carotene.

The authors noted there was a decline in tissue retinol (vitamin A) in the liver and small intestine by two weeks, with a 30% decline by four weeks. But, in the case of the rats fed beta-carotene, there was no effect of benzopyrene on tissue vitamin A levels.

A note of interest is that the benzopyrene had no effect on blood vitamin A levels in both groups of rats during four weeks.

The authors concluded that a high intake of beta-carotene prevented the vitamin A depletion effect of benzopyrene exposure and that further studies appear warranted to determine whether some of the adverse effects of environmental carcinogens, as found in cigarette smoke, charcoal-broiled meats, and industrial wastes, might be alleviated by dietary intervention.

Edes TE, Gysbers DG, Buckley CS, Thornton WH Jr. Exposure to the carcinogen benzopyrene depletes tissue vitamin A: beta-carotene prevents depletion. Nutr Cancer. 1991;15(2):159-66.

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In 1993 Edes and a colleague at the Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, reported in a review that exposure to benzopyrene, a carcinogen (cancer causing substance) causes vitamin A depletion in exposed tissues.

They noted that the effect is apparent while on a vitamin A sufficient diet but significantly, without a decline in serum (blood) Vitamin A. In other words, benzopyrene depleted vitamin A even when the diet was adequate in the vitamin, and this depletion is not apparent in blood tests.

Benzopyrene also known as benzo(a)pyrene is found in coal tar, in automobile exhaust fumes (especially from diesel engines), tobacco smoke, and in charbroiled food. Recent studies have revealed that levels of benzopyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic. (Wikipedia).

Reviewing the studies to date they observed that although these studies involved dietary intake of benzopyrene, it would be realistic to surmise cigarette smoke exposure would have a similar effect.

Edes TE, Gysbers DS. Carcinogen-induced tissue vitamin A depletion. Potential protective advantages of beta-carotene. Ann N Y Acad Sci. 1993 May 28;686:203-11; discussion 211-2. Review.

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Researchers at the Department of Dermatology, Baylor College of Medicine, Houston, Texas, noted that clinical intervention trials found that beta-carotene supplementation evoked no change in incidence of non-melanoma skin cancer.

However, when smokers were supplemented with beta-carotene a significant increase in lung cancer resulted.

Recently, employing a beta-carotene supplemented semi-defined diet, not only was no photoprotective effect found, but significant exacerbation of UV-carcinogenesis occurred. They concluded that at present, beta-carotene use as a dietary supplement for photoprotection should be approached cautiously.

Photochem Photobiol Sci. 2004 Aug;3(8):753-8. Epub 2004 Mar 19.

The subject of beta-carotene supplements increasing lung cancer, especially in smokers, will be covered in a futere article.
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