Unlocking mechanisms of tanning to master protective effect

National report - The prevailing theory of the process of tanning is that ultraviolet B light (UVB) directly stimulates melanocytes.

A deficiency in this process leaves fair-skinned and, most particularly, redheaded persons at a 500- to 1,000-fold increased risk of developing melanoma, compared with those with dark skin or who readily tan.

David Fisher, M.D., Ph.D., and his colleagues at the Dana-Farber Cancer Institute, sought a different explanation. Dr. Fisher hypothesized that at the molecular level, the tanning process begins when UVB stimulates keratinocytes, which secondarily stimulate melanocytes through the melanocyte stimulating hormone (MSH) and the Mc1r ligand.

"From a molecular perspective, the fact that UV has an indirect effect on melanocytes, which is required for tanning, is a fairly significant change from our prior thinking," Dr. Fisher says.

"Understanding this indirect pathway, and the importance of the MSH-Mc1r link, helps to explain why individuals with variant forms of that receptor - i.e. fair-skinned, redheaded people - cannot tan. It is because they have a block right smack in the middle of this pathway. The receptor cannot pass the signal into melanocytes and the pathway to tanning is blocked," Dr. Fisher tells Dermatology Times.

But perhaps the blocked signal could be rescued at a later point in the chemical cascade to activate melanocytes. He chose the cyclic AMP agonist forskolin and applied it topically to the Mc1r deficient mice.

"It worked very potently and essentially turned these mice very, very dark. The pigment was real melanin; it was chemically, histologically and functionally indistinguishable from normal tanning. It is not a permanent tan, but rather like what you would see with UV tanning, it fades over days, just as with sun exposure," Dr. Fisher explains.

He believes there is a good chance the results will translate from mouse to man because the molecular pathways are similar if not identical in both species, and the same gene is responsible for a redheaded person as for a red-haired mouse.

Of mice and men

One significant difference is that mice have the protection of fur and their skin is relatively thin, so forskolin easily penetrates.

"The stratum corneum in human skin is a more formidable barrier than in mice. So it may take some time to find a drug and formulation that will optimally penetrate human skin and hit the target in the melanocyte," he says.

Dr. Fisher is optimistic that this hurdle can be overcome.

"The drug in the paper, forskolin, was literally the very first drug that we tried. There are multiple compounds capable of upregulating cyclic AMP," he adds.

His principle reason for pursuing this line of research, he says, is therapeutic, not cosmetic.

"If you give people a sun block and prevent them from tanning, what you have effectively done is prevented those who might have tanned from tanning, and prevented them from activating the pathway which is most strongly associated with protection against melanoma," Dr. Fisher explains.

He supports use of sun block, and says it clearly has demonstrated efficacy in reducing incidence of squamous cell carcinoma. But he thinks the mechanism by which melanoma develops may be different, and sun block may not afford as much protection. A product that stimulates melanin production might be used as a supplement to sun block, perhaps in the same topical product.

But he acknowledges that some people are likely to use a future product for purely cosmetic reasons, and that too may be a good thing.

"If this would dissuade sun-seeking behavior, from going to the beach or a tanning salon, then there is the possibility of a preventive benefit," he says.

Nix experimentation

One thing that does give him pause is the buzz that has hit the Internet.

People already are sharing tips on how to obtain forskolin and work it into an ointment for topical use.

"We have no safety information; it might be dangerous and we strongly discourage people from such experimentation," Dr. Fisher says.

Clinical trials in humans are necessary to demonstrate both efficacy and safety.

"We didn't see anything that we recognize to be a harmful effect in mice," so that is encouraging.

But mice are short lived compared to humans, and some forms of cancer can take years before they appear.

Dr. Fisher's lab, and a company that he co-founded, are pursing the identification of compounds that can better penetrate human skin and stimulate the production of melanin. They are laying the groundwork for clinical trials to ascertain if such a product will be beneficial.

"Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning" appeared in the September 21 edition of Nature.