7,3',4'-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses α-Melanocyte-Stimulating Hormone-Induced Melanogenesis by Targeting Melanocortin 1 Receptor

Ji Hye Kim; Jae-Eun Lee; Taewon Kim; Myung Hun Yeom; Jun Seong Park; Eric di Luccio; Hanyong Chen; Zigang Dong; Ki Won Lee; Nam Joo Kang

doi:10.3389/fmolb.2020.577284

7,3',4'-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses α-Melanocyte-Stimulating Hormone-Induced Melanogenesis by Targeting Melanocortin 1 Receptor

Front Mol Biosci. 2020 Dec 3:7:577284. doi: 10.3389/fmolb.2020.577284. eCollection 2020.

Authors

Ji Hye Kim^{1

2}, Jae-Eun Lee¹, Taewon Kim¹, Myung Hun Yeom³, Jun Seong Park³, Eric di Luccio⁴, Hanyong Chen⁵, Zigang Dong⁵, Ki Won Lee^{6

7

8}, Nam Joo Kang¹

Affiliations

¹ School of Food Science and Biotechnology, Kyungpook National University, Daegu, South Korea.
² Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, South Korea.
³ Amorepacific Corporation R&D Center, Skin Research Institute, Yongin, South Korea.
⁴ Department of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, South Korea.
⁵ The Hormel Institute, University of Minnesota, Austin, MN, United States.
⁶ World Class University Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.
⁷ Advanced Institutes of Convergence Technology, Seoul National University, Suwon, South Korea.
⁸ Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, South Korea.

Abstract

7,3',4'-Trihydroxyisoflavone (7,3',4'-THIF) is a metabolite of daidzein which is a representative isoflavone found in soybean. Recent studies suggested that 7,3',4'-THIF exerts a hypopigmentary effect in B16F10 cells, however, its underlying molecular mechanisms and specific target protein remain unknown. Here, we found that 7,3',4'-THIF, but not daidzein, inhibited α-melanocyte-stimulating hormone (MSH)-induced intracellular and extracellular melanin production in B16F10 cells by directly targeting melanocortin 1 receptor (MC1R). Western blot data showed that 7,3',4'-THIF inhibited α-MSH-induced tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) expressions through the inhibition of Microphthalmia-associated transcription factor (MITF) expression and cAMP response element-binding (CREB) phosphorylation. 7,3',4'-THIF also inhibited α-MSH-induced dephosphorylation of AKT and phosphorylation of p38 and cAMP-dependent protein kinase (PKA). cAMP and Pull-down assays indicated that 7,3',4'-THIF strongly inhibited forskolin-induced intracellular cAMP production and bound MC1R directly by competing with α-MSH. Moreover, 7,3',4'-THIF inhibited α-MSH-induced intracellular melanin production in human epidermal melanocytes (HEMs). Collectively, these results demonstrate that 7,3',4'-THIF targets MC1R, resulting in the suppression of melanin production, suggesting a protective role for 7,3',4'-THIF against melanogenesis.

Keywords: 3′; 4′-Trihydroxyisoflavone; 7; depigmentation; melanocortin 1 receptor; melanogenesis; α-MSH.