1. Soc. Cosmet. Chem., 25, 61-66 (February 1974) The Presumptive Role of Amino Acid Derivatives and Catecholamines in the Etiology of Vitiligo* ROBERT BRUN, M.D.t Presented May 25, 1972, 14th International Congress ol • Dermatology, Venice Synopsis-Based on the hypothesis that vitiligo could be a phenomenon of the same type as chemically-induced leukoderma, an attempt was made to find some physiological or physiopathological p-hydroxyphenyl derivatives which could be responsible for MELANOGENESIS INHIBITION. Thus, the inhibitory effect of many derivatives of TYROSINE and also sympathomimetic substances on a DOPA-meloanocyte system was tested. The main result was that ADRENALINE (epinephrine) was found to be a strong inhibitor of the Dopa reaction whereas noradrenaline (norepinephrine) was found to have no such effect. Offher strong inhibitors were p-hydroxyphenylpyruvic acid and p-hydroxyphenylcinnamie acid, which could be metabolites of aromatic amino acids. INTRODUCTION In previous research on the mode of action of the hydroquinone deriva- tives in the phenomenon of alepigmentation, it was concluded that these substances were active as competitive inhibitors of tyrosinase (1). In effect, after four applications of p-ethoxyphenol (or monoethylether of hydro- quinone or MEH) the melanocytes of the basal layer of guinea pig skin had already exhausted their reserves of melanin granules, but at this stage the Dopa-reaction was still positive. This clearly demonstrates that in this first step the melanocytes do not produce any more melanin unless the in- hibitory action is arrested. When the h'eatment is prolonged (10-20 days ), melanocytes are no longer found, that is, the Dopa reaction is negative and the repigmentation in vivo *Work supported by Grant 3.606.71, Swiss National Fund for Scientific Researches. tDepartment of Dermatology, Hospital Cantonal, CH-1211 Geneva 4, Switzerland. 61

62 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS can no longer produce itself. Therefore, a vitiligo-like lesion is artifically produced. The examination of guinea pig skin treated with MEH under electron microscopy confirmed the death of the melanoeytes. In effect, Frenk (2) has demonstrated that in the first stage the melanoeytes show important changes and then rapidly die. Furthermore, this author confirmed that this toxic effect is specifically directed against the melanoeytes and that neither the keratinoeytes nor the cells of Langerhans are influenced by this treat- •nent these facts were previously established by our experiences in vivo and through examination under light microscope (3). With our present knowl- edge of vitiligo, it can be verified that, apart from small changes probably due to the absence of protection against ultraviolet light, vitiligo and areas of leukoderma produced artificially by phenol derivatives are similar, if not identical, lesions. Consequently, it seems logical to examine the following hypothesis: "Viti- ligo could be due to the inhibitory action on the tyrosine-tyrosinase system by a phenol derivative for example, a substance produced in the body (physiological or pathological) or a metabolite of such a substance. This product could then provoke the blockage of the melanogenesis (by competi- tion), and after some days of inhibitory action, the death of the melanoeytes. The presence of the inhibitory substance at the level of the melanoeytes could be a consequence of a pathological phenomenon, likewise localized and confined in time." In effect, only several days of inhibition of the melanogenesis can provoke the disappearance of the melanoeytes. Therefore, a transitory pathological phenomenon could be the source of a vitiligo lesion. At the nonprogressive stage, vitiligo could be no more than a sequela of such a pathological phe- nomenon. This hypothesis could equally explain the relatively limited re- suits that have been obtained in the study of vitiligo. The artificial inhibitors previously studied were derivatives of phenol with "para" substituents. It is normal, therefore, to try to discover in which group of substances in the organism an inhibitor of this type could be produced nathologieally. Thus, we have considered two families of compounds which could play an important role in this field tyrosine derivatives on one hand and adrenaline derivatives on the other. It is clear that other related chemi- cal families should also be studied. EXPERIMENTAL A modification of the method of Ijima and Watanabe (4), namely, the in- hibition of the Dopa recation, was used. The modification consisted of the use of unfixed fresh tissue, frozen to -80øC quickly after the biopsy and cut by the cryostat to 8-10/xm. The competitive inhibitors are mixed with the Dopa solution according to a molar ratio "substrat (Dopa)/inhibitor" from 1/1 to 1/• by successive dilution of the inhibitor.