7-desacetoxy-6,7-dehydrogedunin discovered by high-throughput screening system suppresses melanogenesis through ATP-P2X7 signaling inhibition

Abstract

Background: Hyperpigmented skin disorders such as melasma and lentigo are common photoaging diseases that cause cosmetic problems. The pigmentation is usually exacerbated by ultraviolet (UV) radiation, and various factors and pathways are involved in UV-mediated melanogenesis. Adenosine 5'-triphosphate (ATP), a well-known molecular unit of intracellular energy, is also regarded as a mediator of UV-mediated melanogenesis via the P2X7 purinergic receptor.

Objective: To discover natural substances with an anti-melanogenic effect through inhibition of ATP-P2X7 axis by high-throughput screening (HTS).

Methods: Among natural compounds provided by the Korea Chemical Bank, chemical compounds with a P2X7 inhibiting effect were screened through an HTS system. Then the selected compounds were verified for their anti-melanogenic effect after treating primary human epidermal melanocytes (PHEMs) with and without ATP. The expression of MITF, tyrosinase, and PMEL/gp100 was analyzed by Western blot, and melanin content was measured as 405 nm absorbance.

Results: Among 962 natural compounds, 58 showed greater than 80% suppression of YO-PRO-1 fluorescence, representing P2X7 activity. Among them, considering cell viability, chemical stability, and availability, 7-desaxacetoxy-6,7-dehydrogedunin (7DG), a limonoid natural compound, was selected. The expression of MITF, tyrosinase, and PMEL/gp100; tyrosinase enzyme activity; and melanin content, which were increased by ATP treatment were abrogated by 7DG. Even when 7DG was treated in PHEMs without addition of ATP, tyrosinase expression and melanin content were significantly decreased. Hypopigmenting effect of 7DG was confirmed in ex vivo culture of human skins.

Conclusions: 7DG has an anti-melanogenic effect through ATP-P2X7 pathway inhibition and could be a potential skin whitening material.