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Cited by 34melanin and skin pigmentationPharmacological Effects of Natural CompoundsMelanoma and MAPK Pathways

Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways

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Uto, Takuhiro, Ohta, Tomoe, Yamashita, Akihisa, Fujii, Shunsuke, Shoyama, Yukihiro·2019·Medicines
DOI 10.3390/medicines6020068PMC PMC6631415
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Abstract

Background: Liquiritin (LQ) and its aglycone, liquiritigenin (LQG), are major flavonoids in licorice root (Glycyrrhiza spp.). Our preliminary screening identified LQ and LQG, which promote melanin synthesis in the melanoma cells. In this study, we investigated the molecular mechanism of melanin synthesis activated by LQ and LQG. Methods: Murine (B16-F1) and human (HMVII) melanoma cell lines were treated with LQ or LQG. After incubation, melanin contents, intracellular tyrosinase activity, and cell viability were evaluated. Protein levels were determined using Western blotting. Results: LQ and LQG activated melanin synthesis and intracellular tyrosinase activity. The induction of melanin and intracellular tyrosinase activity by LQG was higher than that by LQ. LQ and LQG induced the expression of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. LQ and LQG also enhanced microphthalmia-associated transcription factor (MITF) expression, and cyclic AMP-responsive element-binding protein (CREB) phosphorylation. The phosphorylation of p38 and extracellular signal-regulated kinase (ERK), but not Akt, was significantly increased by LQ or LQG. Furthermore, LQ- or LQG-mediated melanin synthesis was partially blocked by p38 inhibitor (SB203580) and protein kinase A (PKA) inhibitor (H-89); however, ERK kinase (MEK) inhibitor (U0126) and phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002) had no effect. Conclusions: The results suggest that LQ and LQG enhance melanin synthesis by upregulating the expression of melanogenic enzymes, which were activated by p38 and PKA signaling pathways, leading to MITF expression and CREB phosphorylation.

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  • Tyrosinase catalyzes the conversion of L-tyrosine to L-DOPA and then to dopachrome, which is subsequently polymerized spontaneously to melanin via a series of reactions; consequently, tyrosinase is responsible for skin hyperpigmentation.

    “Tyrosinase catalyzes the conversion of L-tyrosine to L-DOPA and then to dopachrome, which is subsequently polymerized spontaneously to melanin via a series of reactions [37]; consequently, tyrosinase is responsible for skin hyperpigmentation.”

    From Licorice (Glycyrrhiza glabra, G. uralensis, and G. inflata) and Their Constituents as Active Cosmeceutical Ingredients (2022) · cites this paper as [37]

    The Introduction (§1) says tyrosinase converts tyrosine to DOPA, but specifies that it oxidizes DOPA to DOPA quinone—not directly to dopachrome. It also describes a subsequent enzyme-catalyzed step rather than the claimed spontaneous polymerization to melanin. The citation is attached to the reaction sequence, so the uncited concluding statement about hyperpigmentation is not part of this verdict. (LLM, conf=0.88)

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Authors
Uto, T., Ohta, T., Yamashita, A., Fujii, S., & Shoyama, Y.
Affiliations
Nagasaki International University (JP)
Corresponding author
Uto, Takuhiro
ORCID
Venue
Medicines
Publisher
MDPI AG
Published
2019-06-22
Volume
6
Issue
2
Pages
68
ISSN
2305-6320 (ISSN-L)
DOI
10.3390/medicines6020068
PMC
PMC6631415
OpenAlex
W2949466171
Cited by
34
References
56
Citations by year
2026: 1 · 2025: 5 · 2024: 5 · 2023: 1 · 2022: 11 · 2021: 5 · 2020: 4 · 2018: 2
FWCI
2.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Medicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for the Promotion of Science (16K18905)
  • Cosmetology Research Foundation (n/a)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Effects of Natural Compounds
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
liquiritin, liquiritigenin, licorice root, flavonoids, melanogenesis, melanoma cells, tyrosinase, TRP-1, tyrosinase-related protein 2, MITF, CREB phosphorylation, p38 MAPK signaling, protein kinase A signaling, ERK signaling

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