34 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS melanoblasts were seen only at the beginning of pigment formation in the area where pigment was found in postuterine life (7). The mesodermal melanoblasts of the skin in man are but rudimen- tarily developed, as in the blue nevus and mongolian spot but in certain animals, such as the mon- keys, guinea pigs, the gray house mouse and the negro fowl, they form an important system of cells. These cells, however, never com- municate with the ectodermal melanoblasts, and they have an origin and period of development different from those of the ecto- dermal cells. They are perhaps akin to those cells that play such an important role in the coldblooded animals. The independence of the development of these two types was especially brought out by Bjoch (7) ' and Steiner-Wourlisch (9). It seems probable from the in- vestigations of Schmidt (11) on reptiles, and especially from those of Kornfeld (12) (Anuren) that in coldblooded animals, pigment cells of mesodermal origin can wander into the epidermis and function there. CHEMISTRY OF PIGMENT (MELANIN) FORMATION Modern investigators of pigment agree that the formation of pigment in the melanoblasts of ectodermal and mesodermal origin is due to the oxidation of a colorless propigment by an enzyme. Fuerth has shown that this melanogen is most prob- ably a cyclic protein component. Fuerth, Przibram, Onslow and others first proposed tyrosine as the melanogen. Free tyrosine has been demonstrated in the circulation of the higher vertebrates, but tyro- sinase has been found in insects and coldblooded animals only. There is no positive evidence that tyrosine is the mother substance of melanin in animals, especially in man. In recent years, a number of Italian arithors (Augeli, Saccardi, Rondoni, Gallerani, Quattrini and Introzzi) have maintained that pyrrole and its derivatives, such as methylindole and scatole, are also propigments. The fallacy of their conclusions has been brought out by the work of Bloch and Schaaf (7) and of Peck (13). Bloch (7) has shown that another aromatic amino acid, namely, B-3-4 dioxyphenylalanine, is the probable propigment in warmblooded ani- mals. The' main support for this assumption is his discovery of the reaction to dioxyphenylalanine in the melanoblasts. This reaction consists in the change of dioxy- phenylalanine into a melanin. Since the reactions take place in .sections of skin, Bloch was able to study microscopically the process of the formation of pigment (dopa reaction). He and his school demonstrated that the reaction to dioxyphenylalanine is specific and enzymatic. It is positive only with B-3-4 dioxyphenylalanine and cannot be elicited with tyrosine, epinephrine or other related dioxy- phenyl derivatives. There is a strict parallelism be- tween the reaction to dioxyphenyl-
THE PIGMENT MELANIN OF THE SKIN AND HAIR 35 alanine and the normal formation of pigment. There is no reaction to dioxyphenylalanine in albinotic skin and vitiligo, while an increase re- action is a necessary accompani- ment and the first evidence of all processes of pigment formation Bloch (7), Peck (14), Miescher (8). Further pigment is the demonstra- tion of pyrocatechol, the natural deaminization product of dioxy- phenylalanine, in the urine of pa- tients with generalized melano carcinoma. One cannot refute the assumption of th.e propigment function of di- .oxyphenylalanine on the ground that its presence has not been demonstrated in the animal body. The deeper understanding of inter- locking chemical processes, such as alcoholic fermentation, has shown that an intermediary substance could easily escape analytic detec- tion and yet form a pivotal phase in the course of the enzymatic process. A great many other criticisms have been raised against Bloch's assumption of a specific dioxy- phenylalanine oxidase. They have been based mainly on the fact that there are other catalytic systems of wider distribution that convert di- oxyphenylalanine into melanin. Polyphenolase, an enzyme of almost ubiquitous occurrence in living mat- ter, acts on polyphenol derivatives, especially orthodiphenol (pyrocate- chol) and its derivatives, such as epinephrine, dioxyphenylalanine, etc., an oxidation that in the pres- ence of amind groups leads to the formation of melanin. The effects of this enzyme are often overshadowed by a concomi- tant heat-stable and therefore non- enzymatic mechanism of oxidation, which is attributed to the iron sys- tem of the cell. The differentiation between these two catalysts has to be based on careful quantitative studies before one is entitled to re- fute the enzymatic character of such reactions. Tyrosinase is another enzyme that can convert dioxyphenylalanine into a melanin. It is found in insects, fungi and higher plants such as po- tatoes. The mechanism, of the formation of melanin from tyrosine by this enzyme has recently been elucidated by Raper (15). He showed that the first step in the oxi- dation of tyrosine is the introduction of a second hydroxy group into the benzene ring yielding ,3-4 dioxy- phenylalanine. The later stages of formation of melanin are due to a less specific mechanism the enzy- matic nature of which is doubtful. Tyrosinase also acts on other mono- phenol derivatives such as para- cresol, tyramine, etc. Unless the enzyme is purified, it also oxidizes the substances mentioned because of contamination with polyphenolase. There is no evidence of the identity of either tyrosinase or polyphen.olase with dioxyphenylalanine oxidase. The oxidation of dioxyphenylalanine by tyrosinase can certainly riot be used as evidence for the identifica- tion of this enzyme with the pigment oxidase, since the outstanding fact remains that the dioxyphenylalanine oxidase acts only on dioxyphenyl-
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