RESUMO
16-hydroxy-9-oxo-10E,12E,14E-octadecatrienoic acid, also known as Corchorifatty acid B (CFAB), is isolated from the ethanol extracts of the aerial parts of Melissa officinalis Linné (Labiatae) and exhibits inhibitory effects on cellular pigmentation in both human melanocytes and mouse melanoma B16 cells. CFAB specifically decreases cellular melanin by most likely inducing rapid degradation of tyrosinase in B16 cells. Interestingly, unlike other reagents that promote degradation of tyrosinase in proteasomes or lysosomes, neither proteasomal nor lysosomal inhibitors can halt CFAB-induced tyrosinase degradation. Only brefeldin A, which specifically inhibits protein transport from the endoplasmic reticulum to the Golgi complex, can effectively impede CFAB-induced tyrosinase decrease. These results suggest that CFAB-induced tyrosinase decrease occurs in post-Golgi compartments but not in proteasomal or lysosomal compartments. Taken together, CFAB is a unique reagent that primarily accelerates tyrosinase decrease by a mechanism that differs from those considered for other hypopigmentation reagents currently reported.
Assuntos
Ácidos Linolênicos/farmacologia , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melissa/química , Cloreto de Amônio/farmacologia , Animais , Brefeldina A/farmacologia , Células Cultivadas , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Melanócitos/metabolismo , Melanoma Experimental , Glicoproteínas de Membrana/metabolismo , Camundongos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/metabolismo , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Pigmentação da Pele/efeitos dos fármacosRESUMO
Tyrosinase, a melanosomal membrane protein containing copper, is a key enzyme for melanin synthesis in melanocytes. Inulavosin inhibits melanogenesis by enhancing a degradation of tyrosinase in lysosomes. However, the mechanism by which inulavosin redirects tyrosinase to lysosomes is yet unknown. The analyses of structure-activity relationship of inulavosin and its benzo-derivatives reveal that the hydroxyl and the methyl groups play a critical role in their inhibitory activity. Intriguingly, the docking studies to tyrosinase suggest that the compounds showing inhibitory activity bind through hydrophobic interactions to the cavity of tyrosinase below which the copper-binding sites are located. This cavity is proposed to be required for the association with a chaperon that assists in copper loading to tyrosinase in Streptomyces antibioticus. Inulavosin and its benzo-derivatives may compete with the copper chaperon and result in a lysosomal mistargeting of apo-tyrosinase that has a conformational defect.