bisabolangelone and Hyperpigmentation

Microphthalmia-associated transcription factor (MITF) is inducible in response to cAMP and has a pivotal role in the melanocyte-specific expression of tyrosinase for skin pigmentation. Here we suggest that the cAMP-binding site of protein kinase A (PKA) is a target in the inhibition of the melanogenic process in melanocytes, as evidenced from the molecular mechanism of small molecules such as bisabolangelone (BISA) and Rp-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMPS). BISA is a sesquiterpene constituent of Angelica koreana, a plant of the Umbelliferae family, whose roots are used as an alternative medicine. BISA competitively inhibited cAMP binding to the regulatory subunit of PKA and fitted into the cAMP-binding site on the crystal structure of PKA under the most energetically favorable simulation. In α-melanocyte-stimulating hormone (α-MSH)-activated melanocytes, BISA and Rp-cAMPS nullified cAMP-dependent PKA activation, dissociating catalytic subunits from an inactive holoenzyme complex. They resultantly inhibited cellular phosphorylation of the cAMP-responsive element-binding protein (CREB) or another transcription factor SOX9, thus downregulating the expression of MITF or the tyrosinase gene with decreased melanin production. Taken together, this study defined the antimelanogenic mechanism of BISA or Rp-cAMPS with a notable implication of the cAMP-binding site of PKA as a putative target ameliorating melanocyte-specific hyperpigmented disorder.

Topics: Angelica; Binding Sites; Cells, Cultured; CREB-Binding Protein; Crystallography, X-Ray; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Gene Expression; Humans; Hyperpigmentation; Melanins; Melanocytes; Microphthalmia-Associated Transcription Factor; Phosphorylation; Phytotherapy; Sesquiterpenes; SOX9 Transcription Factor

Tyrosinase is a key enzyme in the biosynthetic pathway of melanin pigments. Abnormal accumulation of melanin pigments causes melasma, freckles, and senile lentigo, which can be substantially ameliorated by treatment with arbutin or other tyrosinase inhibitors. In this study, roots of Angelica koreana Maxim. (Umbelliferae) inhibited melanin production in α-melanocyte stimulating hormone ( α-MSH)-activated B16 melanoma cells or melan-a melanocytes. To elucidate the hypopigmenting principle of A. koreana, the plant extracts were subjected to bioassay-guided phytochemical analysis, resulting in the identification of bisabolangelone. Bisabolangelone dose-dependently inhibited α-MSH-induced melanin production in B16 or melan-a cells with IC(15) values of 9-17 µM. The positive control arbutin also inhibited melanin production in B16 cells with an IC(50) value of 317 µM. Bisabolangelone suppressed α-MSH-inducible protein levels of tyrosinase in B16 cells but could not significantly inhibit the catalytic activity of cell-free tyrosinase. Taken together, this study indicates that bisabolangelone is the primary hypopigmenting principle of A. koreana and may have pharmacological potential in the melanin-associated hyperpigmentation disorders.

Topics: alpha-MSH; Angelica; Animals; Cell Line; Cell Line, Tumor; Dermatologic Agents; Dose-Response Relationship, Drug; Hyperpigmentation; Inhibitory Concentration 50; MART-1 Antigen; Melanins; Melanocytes; Melanoma, Experimental; Monophenol Monooxygenase; Phytotherapy; Plant Extracts; Plant Roots; Sesquiterpenes; Skin