Are tyrosinase inhibitors in sunscreens and cosmetics enhancing UV carcinogenicity? (2015)

Melanin is the pigment synthesized in the skin responsible for the adaptive pigmentation in humans which protects from the dangerous and possible carcinogenic effects of UV rays present in the sunlight 1. The main enzyme synthesizing melanin in the skin melanocytes is tyrosinase whose natural substrate is tyrosine, but can accept as substrates a large number of aromatic compounds (S1) which may interfere with the production of melanin. A larger number of aromatic and non-aromatic compounds inhibit competitively or not competitively melanin activity reducing or abolishing the melanin formation, reducing or preventing the sun tanning of the skin 2. The vast majority of the organic UV absorbers present in the sunscreens are aromatic compounds (AC), and about one-third are phenols present at high concentration between 4 and 15% (www.tga.health.gov.au/docs/html/argom.htm). AC are frequently present also in other cosmetics, in drugs and, in general, in products with which humans are in contact daily. Most of these compounds were not properly tested for their effects on tyrosinase, and particularly intriguing is their possible presence in sunscreen products. Salicylic acid (and presumably salicylates), para-aminobenzoic acid (PABA) and benzoic acid, largely present in sunscreens or other skin products, are in fact established tyrosinase inhibitors (S2–S4). In the last years, many researchers have epidemiologically studied whether sunscreen use influences the malignant melanoma (MM) incidence upon sun exposure. Surprisingly, most of the researchers (3-5; S5–S11) observed that sunscreen users have a higher incidence of MM than non-users although at present a considerable controversy exists. Huncharek and Kupelnick 6, in a meta-analysis of these papers, have concluded that sunscreen use does not increase nor diminish the MM incidence, a rather unexpected conclusion given that sunscreens are supposed to filter UV light which is claimed as the main cause of MM incidence. In a previous paper 7, we have suggested that these hard to explain epidemiological data may be explained by the presence in sunscreens and in other cosmetic products of tyrosinase inhibitors impairing the melanin synthesis which shields the skin from the dangerous action of UV rays (Fig. 1). We have therefore decided to test ten aromatic organic UV absorbers present in sunscreen formulations and cosmetics. It may be seen in Fig. S1 that five of the ten organic UV absorbers tested are almost insoluble in water, and therefore, their activity on tyrosinase cannot be appreciated in our experiments and their activity in vivo, in which the conditions are very different, remains unknown. Three of the five remaining compounds, Uvinul® D50, Uvinul® M40 and Uvinul® MS40 (BASF, Ludwigshafen, Germany), are tyrosinase inhibitors. It is noteworthy that Uvinul® D50 is one of the most potent tyrosinase inhibitors ever tested with a potency comparable to that of 4-n-butylresorcinol (Fig. 2a,b). The other two are less potent and inhibit tyrosinase at micromolar and millimolar concentrations (Fig. 2c,d). Uvinul® MS40 suppressed tyrosinase activity of approximately 33% at 1 and 3 mm. Our data demonstrate that other compounds, beside those already reported, that are PABA, salicylic acid and benzoic acid, may inhibit tyrosinase presumably hampering tanning. Two of the organic UV absorbers, Uvinul® M40 and MS40, are used prevalently in the sunscreen products at high concentration. The third product, Uvinul® D50, is not present in the sunscreens, at least in USA and Europe as it was not authorized by the Food and Drug Administration and the European authorities because it has potent oestrogenic effects (S12), but incredibly it is present in an enormous number of cosmetics, soaps, shampoos, etc. and therefore may be used daily for whole life. Uvinul® D50 is incredibly potent, few micrograms inhibiting totally the tyrosinase. Even if they are effective in filtering the UV rays, the likely inhibition of the melanin synthesis in the skin is probably harmful increasing the genetic damage produced by UV rays and contributing to the continuous raising trend of MM. This can be counterintuitive if considering a possible compensatory effect due to the sunscreen, but it is realistic to hypothesize that the compensatory effect is not complete. Due to the long human evolution pathway 8, skin melanin should have, at least in theory, a much higher efficacy (UV absorbing and protecting properties) than anthropogenic sunscreens. The relationship between melanoma and sunscreen use is difficult to make. This hypothesis would be far less speculative if in vivo data would be available. First of all, the real concentration of tyrosinase inhibitor sunscreens at the level of the basal lamina should be measured using microdialysis, and then, the effect of these compounds on melanoma induced by carcinogenesis protocols should be tested in mice. Sunscreens are devised to protect us from the harmful effects of UV rays: it seems incredible and paradoxical that these products are not tested to evaluate their activity on tyrosinase, the enzyme that provides us with the natural protection afforded by melanin. It is our opinion that its use should be banned in any product that may enter in contact with human skin. Alternatively, advanced formulation strategies, which contemplate the organic UV absorbers encapsulation or inclusion with no or minimal release, should be strongly promoted. These novel formulation approaches permit to reduce or completely eliminate the contact between these molecules and the skin avoiding absorption. Encapsulated sunscreens remain efficient UV absorbers on the skin surface 9, 10. Giorgio Morpurgo (Y, B), Luigi Catacuzzeno (Y), Sara Peruzzi (X, A), Paolo Blasi (Z, B) and Bernard Fioretti (X, Y, B). The authors have declared no conflicting interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.