Previously, we demonstrated that skin cells metabolize melatonin to 6-hydroxymelatonin, N<sup>1</sup>-acetyl- N<sup>2</sup>-formyl-5-methoxykynuramine and 5-methoxytryptamine. In this study, we determined that N1- acetyl-5-methoxykynuramine (AMK) is endogenously produced in the human epidermis from melatoninthroughthe kynuricpathway.Theepidermal content ofAMK(averagefrom13subjects) is 0.99±0.21 ng/mg protein, being significantly higher in African Americans (1.50±0.36 ng/mg protein) than in Caucasians (0.56±0.09 ng/mg protein). It is especially high in young African Americans. The levels do not differ significantly between males and females. In vitro testing using HaCaT keratinocytes has shown that exogenously added melatonin is metabolized to AMK in a dose dependent manner with a V<inf>max</inf> = 388 pg/million cells and K<inf>m</inf> = 185 μM. AMK production is higher in melanized than in amelanoticmelanomacells. Testing ofDNAincorporationshowsthatAMKhasantiproliferative effects in HaCaT and SKMEL-188 cells (nonpigmented and pigmented). AMK also inhibits growth of normal melanocytesbuthasnosignificant effectonmelanogenesisor cellmorphology.Thesefindings indicate that antiproliferative effects of AMK are not related to melanin pigmentation. In summary, we show for the first time that AMK is produced endogenously in the human epidermis, that its production is affected by melanin skin pigmentation, and that AMK exhibits antiproliferative effects in cultured keratinocytes and melanoma cells.
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