Melanogenesis inhibitors from the rhizomes of Alpinia officinarum in B16 melanoma cells

doi:10.1016/j.bmc.2009.06.057

Bioorganic & Medicinal Chemistry

Volume 17, Issue 16, 15 August 2009, Pages 6048-6053

https://doi.org/10.1016/j.bmc.2009.06.057 Get rights and content

Abstract

The 80% aqueous acetone extract from the rhizomes of Alpinia officinarum, a Chinese medicinal herb, were found to inhibit melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. Among the constituents isolated, four diarylheptanoids [5-hydroxy-1,7-diphenyl-3-heptanone, 7-(4^″-hydroxy-3^″-methoxyphenyl)-1-phenylhept-4-en-3-one, 5-hydroxy-7-(4^″-hydroxy-3^″-methoxyphenyl)-1-phenyl-3-heptanone, and 3,5-dihydroxy-1,7-diphenylheptane] and two flavonol constituents (kaempferide and galangin) inhibited melanogenesis with IC₅₀ values of 10–48 μM, and several structural requirements of the active constituents for the inhibition were clarified. In addition, 7-(4^″-hydroxy-3^″-methoxyphenyl)-1-phenylhept-4-en-3-one, kaempferide, and galangin inhibited mRNA expression of tyrosinase and tyrosinase-related proteins-1 and -2, and the protein level of a microphthalmia-associated transcription factor.

Graphical abstract

The 80% aqueous acetone extract and four diarylheptanoids [5-hydroxy-1,7-diphenyl-3-heptanone, 7-(4′′-hydroxy-3′′-methoxyphenyl)-1-phenylhept-4-en-3-one, 5-hydroxy-7-(4′′-hydroxy-3′′-methoxyphenyl)-1-phenyl-3-heptanone, and 3,5-dihydroxy-1,7-diphenylheptane] and two flavonol constituents (kaempferide and galangin) inhibited melanogenesis with IC₅₀ values of 10–48 μM, and several structural requirements of the active constituents for the inhibition were clarified. In addition, 7-(4′′-hydroxy-3′′-methoxyphenyl)-1-phenylhept-4-en-3-one, kaempferide, and galangin inhibited mRNA expression of tyrosinase and tyrosinase-related proteins-1 and -2, and the protein level of a microphthalmia-associated transcription factor.

Introduction

Melanin production is principally responsible for skin color, and melanin pigmentation is a major defense mechanism against ultraviolet rays from the sun. Melanin biosynthesis proceeds through a complex series of enzymatic and chemical reactions in melanocytes.1, 2, 3, 4 The synthesis of melanin starts from the conversion of the amino acid l-tyrosine to dopaquinone by tyrosinase, the enzyme catalyzing the rate-limiting step of melanin biosynthesis.² This tyrosinase process is involved in abnormal accumulation of melanin pigments (hyperpigmentation).5, 6 Therefore, tyrosinase inhibitors such as kojic acid and albutin have been established as important constituents of cosmetic products and depigmenting agents for the treatment of hyperpigmentation.7, 8

In the course of our studies on the bioactive constituents of natural medicines, we found that the 80% acetone extract from the dried rhizomes of Alpinia officinarum HANCE showed inhibitory effects on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells. The Zingiberaceae plant A. officinarum has been cultivated in southern China and Taiwan, and the rhizomes of this plant are used as a spice and as a traditional medicine for several purposes, such as a stomachic and carminative, in China. In chemical studies of these rhizomes, the isolation and structural determinations of monoterpenes,⁹ diarylheptanoids,10, 11, 12, 13, 14, 15, 16 flavonoids,17, 18, 19 phenylpropanoids,20, 21 and neolignans²² have been reported. With regard to the biological effects, antiemetic,¹⁶ antioxidant,21, 22 and anti-genotoxic activities²³ and inhibition of prostaglandin and leukotriene biosynthesis,14, 24 pancreatic lipase,19, 25 5α-reductase,²⁶ and of nitric oxide production,27, 28, 29 etc. were reported. Lu et al. reported that the extract of A. officinarum and galangin (6) inhibited the enzyme activity of mushroom tyrosinase and melanogenesis in B16 melanoma cells.³⁰ However, the effects of other constituents of this natural medicine on melanogenesis in B16 melanoma cells have not been reported to the best of our knowledge.

In this paper, we describe the effects of constituents (1–9) from the rhizomes of A. officinarum²⁹ and related flavonoids (10, 11)31, 32 on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells and on the enzyme activity of mushroom tyrosinase.

Section snippets

Effects of constituents (1–9) and related flavonoids (10, 11) on melanogenesis

Melanocytes can be stimulated by many effectors including ultraviolet radiation³³ and α-melanocyte-stimulating hormone (α-MSH).³⁴ It is generally accepted that the cAMP pathway plays a key role in the regulation of melanogenesis, and cAMP is involved in α-MSH-stimulated signal transduction.34, 35 In the present study, we used the phosphodiesterase inhibitor theophylline³⁶ to stimulate B16 melanoma 4A5 cells. As shown in Table 1, the 80% acetone extract significantly inhibited melanogenesis with

Conclusion

The 80% acetone extract of the rhizomes of A. officinarum were found to inhibit melanogenesis in theophylline-stimulated mouse B16 melanoa 4A5 cells. Among the constituents isolated, four diarylheptanoids (1–4) and two flavonol constituents (5, 6) substantially inhibited melanogenesis with IC₅₀ values of 10–48 μM, and an enone moiety in 2 and the 2,3-double bond in 6 are important for more potent activity. In addition, 2, 5, and 6 inhibited the mRNA expression of tyrosinase, TRP-1 and -2, and

Extraction and isolation of 1–9 from A. officinarum

The extraction and isolation of compounds 1–9 were described in our previous report.²⁹ Briefly, the dried rhizomes of A. officinarum (3.0 kg) were extracted three times with 80% aqueous acetone at room temperature. The extract (9.6% from this natural medicine) was partitioned into an ethyl acetate (EtOAc)–water mixture to furnish the EtOAc-soluble fraction (5.2%) and water-soluble fraction (4.4%). The EtOAc-soluble fraction, which showed potent activity (Table 1), was subjected to normal-phase

Acknowledgments

This research was supported by the 21st COE Program, Academic Frontier Project, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Melanogenesis inhibitors from the rhizomes of Alpinia officinarum in B16 melanoma cells

Abstract

Graphical abstract

Introduction

Section snippets

Effects of constituents (1–9) and related flavonoids (10, 11) on melanogenesis

Conclusion

Extraction and isolation of 1–9 from A. officinarum

Acknowledgments

J. Invest. Dermatol.

Int. J. Biochem.

Exp. Cell. Res.

Mutat. Res.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Invest. Dermatol. Symp. Proc.

Trends Mol. Med.

Med. Res. Rev.

Pigment Cell Res.

Pigment Cell Res.

Am. J. Clin. Dermatol.

Phytother. Res.

Food Sci. Technol. Res.

Yakugaku Zasshi

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

J. Nat. Prod.

Chem. Pharm. Bull.

Planta Med.

Biol. Pharm. Bull.