Highlights
- •ATP is known to serve as a mediator of UV-induced melanogenesis.
- •P2×7 receptor transduces extracellular ATP signal in melanocytes.
- •7-desaxacetoxy-6,7-dehydrogedunin (7DG) has P2×7 inhibiting effect.
- •7DG showed anti-melanogenic effect by suppressing ATP-P2×7 signal.
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.
Abbreviations:
7DG (7-desacetoxy-6,7-dehydrogedunin), ATP (adenosine 5′-triphosphate), α-MSH (α-melanocyte-stimulating hormone), DMEM (Dulbecco's Modified Eagle Medium), Gp100 (glycoprotein 100), HBSS (Hanks' Balanced Salt Solution), HOS (Human osteosarcoma), HTS (high throughput screening), MITF (Microphthalmia-associated transcription factor), MTT assay ([4,5-dimethylthiazol-2-yl]− 2,5-diphenyltrazolium bromide assay), PHDF (primary human dermal fibroblast), PHEK (primary human epidermal keratinocyte), PHEM (primary human epidermal melanocyte), PKA (cAMP-dependent protein kinase A), PKC (protein kinase C), UV (ultraviolet), UVB (ultraviolet B)Keywords
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Article info
Publication history
Published online: December 29, 2022
Accepted:
December 27,
2022
Received in revised form:
November 25,
2022
Received:
May 29,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
