130 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS is utilized to produce pheomelanin. It can be seen that regardless of the final pigment the basic energy originates from tyrosinase. Since neither a pheomelanin nor an intermediate has been identified in human hair, this system is hypothetical. If studies in other animals apply to the human the pigment or pigments are probably derived from 3-hydroxykynurenine. In one redheaded patient (10) the areas of white hair became brown when chloroquine diphosphate was stopped. It seems likely that in these areas the pheomelanin system was destroyed. This removed the switch mecha- nism and the tyrosinase system produced melanin. Excessive inhibition of the pheomelanin system is likely to result in black hair rather than per- manently white hair. A red iron containing pigment, trichosiderin was isolated by Rothman and Flesch (14). The chemical structure of this pigment has not been identified. There is still uncertainty whether this is a natural pigment or a compound formed during the process of extraction. NORMAL CONTROL OF PIGMENT FORMATION Variation in the shade of hair color at different ages makes it obvious that pigment formation is not constant. Considering the entire metabolic process involved there are many areas where pigment production can be influenced. Most basic are the factors controlling the activity of the Golgi apparatus in laying down the protein matrix of the granule. Mito- chondria may play an important role in providing energy for the protein synthesis. Tyrosinase activity depends upon the availability of tyrosine, rate of tyrosinase synthesis and balance between activators and inhibitors. We must presume that the same factors will apply to the enzyme which converts tryptophan to aminophenol. Some of these processes are mod- erately well known but others are almost pure conjecture. Since there are many apparent mechanisms to influence pigment forma- tion it is logical to ask whether they are all utilized or whether the effects are always accomplished through the same chanel. Most alterations in hair color result in loss of pigment but it is possible to darken the color of the hair. There is a decreasing tyrosinase activity as hair becomes gray. The early stages of the growing hair have no tyrosinase activity, the adult hair is very active and pigment formation ceases just before the hair stops growing (15). White hair from one individual contained no detectable pigment granules (4). It appears that the hair has both fluctuation in enzyme activity and complete cessation of granule formation. It is un- likely that the melanocytes will be destroyed when hair turns white. Hair which is regrowing in alopecia areata may remain white for months. Mi- croscopically this hair resembles anagen IV hair (16). Hair at this stage

NATURAL COLOR PIGMENTS OF THE HAIR 13l should be producing melanin. This appears to represent repression of hair growth with greater repression of pigment formation. Monobenzylether of hydroquinone and guanofuracin are two compounds which can produce depigmentation. Guanofuracin produced depigmentation of the eye- lashes when used in the eyes (17). Histologic studies of skin following application of these compounds suggest that they interfere with basic granule formation. The Vogt-Koyanagi syndrome and some reactions of monobenzylether of hydroquinone and guanofuracin involve an allergic mechanism. The antigen is presumed to be melanin. These reactions may lead to widespread depigmentation of skin and hair. Phenylthiourea and alphanaphthylthiourea are excellent inhibitors of tyrosinase. They probably produce depigmentation by enzyme inhibition. Molybdenum interferes with copper. Depigmentation occurs because tyrosinase is a copper protein. The mechanism of vitiligo is unknown. From the facts that are known it appears to differ from the above mechanisms. Other examples could be cited. It seems obvious that normal variations, dis- eases and chemicals resulting in depigmentation do not function by the same mechanism. Increase in hair color appears to involve a single mechanism, increase of tyrosinase activity. This is frequently coupled with hair growth so that the metabolism of the entire hair follicle may also respond. Chronic irritation of the skin, rubbing or biting, leads to the increased formation and darkening of hair. The use of psoralens, photosensitizers, and sunlight will result in increased length and darkening of the hair. It is possible to repigment some gray hair in this way. Inflammation of the scalp, such as a boil, in a person with gray hair may lead to the production of a small patch of dark hair (18). Simple inflammation of the scalp from any cause will tend to increase growth and darkness of hair. This response provides a limiting factor of sorts to strong bleaching agents. When a bleach irritates the skin the dark roots appear more rapidly. How likely is a chemical to interfere with normal hair color? Mono- benzylether of hydroquinone is used as a depigmenting agent. The pso- talens are photosensitizers and their darkening effect was predicted. Chloro- quine diphosphate, hydroxychloroquine diphosphate, guanofuracin, me- phenesin carbamate and diodoquin are therapeutic compounds whose depigmenting effect on the hair was unexpected. There are other poisonous materials which cause alepigmentation of the hair. None of these prepara- tions has been completely investigated in human hair. A practicing physician cannot be expected to continue a therapeutic agent producing a marked cosmetic defect. I am aware, however, of dark blond to brown haired patients in whom chloroquine diphosphate has produced platinum blond bleaching of the scalp hair, eyebrows, eyelashes and pubic hair. Chloroquine diphosphate in adequate dosage for an adequate time would