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

  • Author Footnotes
    1 These authors contributed equally to this work.
    Sujin Park
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Eun Ju Choi
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ji Young Kim
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Eun Jung Lee
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Yu Jeong Bae
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Seol Hwa Seong
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Jinu Lee
    Correspondence
    Corresponding authors.
    Affiliations
    College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
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  • Sang Ho Oh
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
Published:December 29, 2022DOI:https://doi.org/10.1016/j.jdermsci.2022.12.011

      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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