Anti-melanogenic Activity of Auraptene via ERK-mediated MITF Downregulation

Auraptene is the most abundant naturally occurring geranyloxycoumarin. It is primarily isolated from plants belonging to the Rutaceae family, many of which, such as citrus fruits, are used as food in many countries. Auraptene is a biologically active secondary metabolite that possesses valuable properties. The aim of this study was to investigate the in vitro inhibitory effects of auraptene on melanogenesis and the enzymes associated with it, such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, in B16F10 murine melanoma cells. We found that auraptene significantly attenuated melanin synthesis and reduced the activity of intracellular tyrosinase, which was the rate-limiting melanogenic enzyme. Western blotting analysis showed that auraptene decreased tyrosinase and TRP-2 protein expression. In addition, auraptene significantly decreased the expression of microphthalmia-associated transcription factor (MITF), a key regulator of melanogenesis. Extracellular signal-regulated kinase (ERK) activation has been reported to be involved in the inhibition of melanogenesis. Thus, we next investigated if the hypopigmentary effects of auraptene were related to the activation of ERK. Auraptene was found to induce phosphorylation of ERK in a dose-dependent manner. Our results suggest that auraptene inhibits melanogenesis by activating the ERK pathway-mediated suppression of MITF and its downstream target genes, including tyrosinase. Therefore, auraptene may be used as a whitening agent in the development of functional cosmetics.