THE IN-VIVO MELANOCYTOTOXICITY AND DEPIGMENTING POTENCY OF N-2,4-ACETOXYPHENYL THIOETHYL ACETAMIDE IN THE SKIN AND HAIR

It has been shown previously that N-acetyl-4-S-cysteaminylphenol (N-Ac -4-S-CAP) is a tyrosinase substrate and a potent depigmenting agent of dark skin and black hair. The present study evaluated the depigmentin g potency of an acetyl derivative of N-Ac-4-S-CAP, N-2, 4-acetoxypheny l thioethyl acetamide (NAP-TEA) in the skin and hair. We tested for (i ) in vitro metabolites in the skin after topical application, and (ii) in vivo depigmenting potency in the skin and hair, We found that NAPT EA was stable in water, but was converted to N-Ac-4-S-CAP after topica l application to human skin. Therefore, although NAP-TEA was not a tyr osinase substrate, it could react with tyrosinase after being converte d to N-Ac-4-S-CAP by O-deacetylation in vivo. NAP-TEA produced marked depigmentation of dark skin (Yucatan pig) after daily topical applicat ion, When given by intraperitoneal injection, it resulted in complete loss of hair colour (white) grown at the epilated site in adult C57 bl ack mice after daily administration for 10 days, and incomplete loss o f coat colour (silver grey) in newborn C57 black mice after a single a dministration. The depigmentation of the skin and hair was reversible. Split-dopa preparation acid electron microscopy indicated that this d epigmentation is primarily related to (i) a marked decrease in the num ber of functioning melanocytes and melanized melanosomes, (ii) a decre ase in the number of melanosomes transferred to keratinocytes, and (ii i) selective degeneration/inactivation of melanocytes, and deposition of melanin-like material in the Golgi cisternae, coated vesicles and m elanosomes, where tyrosinase is reported to be located. We propose the NAP-TEA is converted in vivo to N-Ac-4-S-CAP which, via interaction w ith tyrosinase, causes reversible depigmentation of the skin and hair.