panax ginseng ( ginseng ) has been used traditionally in eastern asia over thousands of years .
it has been used orally to treat various diseases including hypertension , diabetes mellitus , liver and kidney dysfunction , mental disorders , and postmenopausal disorders .
in addition , topical applications have also been used to heal wounds and reduce skin inflammation . in the past few decades
, it has been proved that ginseng extracts actually show a wide range of effects against human diseases .
their potential therapeutic effects have been mainly attributed to its immunomodulatory , neuroprotective , antioxidative , antitumor , and hepatoprotective activities .
ginseng contains a number of active ingredients including ginsenosides , polysaccharides , phytosterols , peptides , polyacetylenes , fatty acids , and polyacetylenic alcohols , which have different effects on carbohydrate and lipid metabolism , cognition , angiogenesis , and the neuroendocrine , immune , cardiovascular , and central nervous systems . among the active constituents of ginseng ,
ginsenosides are known to be the major biologically active components of ginseng and the most widely studied .
several studies have shown that ginsenosides play important roles in the pharmacological effects of ginseng .
. however , ginseng contains other constituents , including ginsenoyne , phenolic compounds , polyacetylenes , sesquiterpenes , methoxypyrazine , alkylpyrazine derivatives , sesquiterpene alcohols , panasinsanols , and -carboline .
white ginseng is peeled , dried , ginseng root and red ginseng is produced by steaming fresh ginseng root at 98100c for 23  h , and then drying until the moisture content is < 15% .
red and white ginseng have both been shown to have immunomodulatory , anti - inflammatory , antioxidant , and antiatopic activities . moreover ,
red ginseng has been reported to have more potent pharmacological activities than white ginseng in some respects [ 2022 ] .
the differences in biological activities between red and white ginseng are caused by the chemical changes of ginsenosides after the steaming process .
steaming partially converts the original ginsenosides to deglycoslated derivatives . as a result , the species and amounts of ginsenosides are quite different based on the processing method used .
chu et  al   showed that a total of 53 and 43 compounds were tentatively identified in white ginseng and red ginseng samples , respectively .
the featured compounds are mainly malonyl ginsenosides in white ginseng , and decarboxyl products of mal - ginsenosides and the dehydrated compounds from polar ginsenosides were characteristic in red ginseng .
it is interesting that ginsenosides show a wide variety of biological activities , although the absorption rates from orally administered intact ginsenosides are very low . in the human intestinal tract ,
thus , the pharmacological actions of these ginsenosides have been closely related to their biotransformation by human intestinal bacteria . in this context
several studies showed that the transformation of ginsenosides into deglycosylated ginsenosides is needed to increase ginseng 's effectiveness in  vivo 
 .
abnormal changes in skin color induce significant cosmetic problems with a negative effect on quality of life .
there are two groups of pigmentary disorders : disorders of the quantitative and qualitative distribution of normal pigment and the abnormal presence of exogenous or endogenous pigments in the skin .
hyperpigmentation - related diseases include melasma , lentigines , nevus , ephelis , freckles , postinflammatory hyperpigmentation , and age spots .
postinflammatory hyperpigmentation appears in many skin conditions , including acne , eczema , and contact dermatitis .
skin color is determined by various factors including melanin content , oxygenation state of hemoglobin in capillary vessels , carotenoid content , water content , and organization of collagen fibers in the dermis . among these factors , melanin is the major determinant of skin color . in this context ,
melanogenesis is a biochemical pathway responsible for melanin synthesis that is controlled by complex regulatory mechanisms .
melanogenesis occurs in melanocytes confined in separate cytoplasmic organelles called melanosomes , which contain key enzymes of melanogenesis .
differences in skin color are related to the size , number , shape , and distribution of melanosomes , whereas melanocyte density typically remains relatively constant  .
although tyrosinase is the key regulatory enzyme of melanogenesis , tyrosinase - related protein ( trp)-1 , dopachrome tautomerase ( dct / trp2 ) , and melanosomal matrix proteins ( pmel17 , mart-1 ) carry out important roles in regulating melanogenesis .
the genes of tyrosinase , trp-1 , and dct contain common transcription starting sites , the microphthalmia - associated transcription factor ( mitf ) binding sites .
the intracellular signal transduction pathways of protein kinase c , cyclic amp ( camp ) , and nitrogen oxide are involved in the regulation of melanogenesis .
various endogenous and exogenous factors , such as estrogen and ultraviolet ( uv ) radiation , affect melanogenesis via signal transduction pathways .
these endogenous / exogenous factors exert their actions directly on melanocytes or indirectly via surrounding skin cells .
melanocytes , keratinocytes , dermal fibroblasts , and other skin cells communicate with each other by factors that are secreted and cell  cell contacts .
it has been shown that the interactions between keratinocytes and melanocytes are critical in the regulation of melanogenesis .
in addition , dermal factors have been found to be involved in the regulation of melanogenesis . at the same time , stimulated melanocytes secret a number of signal molecules targeting not only keratinocytes but also skin immune cells .
soluble factors released by melanocytes include proinflammatory cytokines and chemokines such as interleukin ( il)-1/1 , il-6 , il-8 il-10 , tumor necrosis factor ( tnf)- , transforming growth factor ( tgf)- , catecholamines , eicosanoids , serotonin , -melanocyte stimulating factor ( -msh ) , and nitric oxide ( no ) .
a variety of hypopigmenting agents including hydroquinone , arbutin , tretinoin , kojic acid , azelaic acid , vitamin c , n - acetylglucosamine , niacinamide , linoleic acid , ellagic acid , methimazole , dioic acid , soy extract , licorice extract , rucinol , and glycolic acid have been used alone or in combination to treat abnormal hyperpigmentation .
these agents can interfere with the pigmentation process at several different steps of skin pigmentation .
however , the treatment of hyperpigmented conditions still remains challenging and the results are often discouraging .
thus there is a need for novel skin - whitening agents that are highly effective and tolerable . in this article
, we review recent reports investigating the skin - whitening effect of ginseng and its components and the underlying mechanisms of action , and then discuss their potential as candidates for novel skin - whitening agents .
p.  ginseng is one of the most widely used medicinal plants in traditional oriental medicine . over thousands of years
, it has been used to improve the overall condition of skin , as well as to treat a wide variety of diseases . however
, genuine scientific approaches to clarify the efficacy of ginseng in skin have only been made in recent years .
several reports have shown that ginseng extract , powder , or some other constituents could inhibit melanogenesis in  vitro and in  vivo . table  1 summarizes the direct effects of ginseng and its components on skin color and key enzymes involved in melanogenesis .
song et  al reported that red ginseng powder improved melasma in a human clinical trial .
they orally administered korean red ginseng powder for 24 weeks to female patients with melasma .
after 24 weeks , the melasma area and severity index score decreased and melasma quality of life scale showed improvement in 91% of patients .
in addition , 74% of the patients showed some improvement on the patient- and investigator - rated global improvement scales .
most of reports investigating the antimelanogenic effect of ginseng were conducted in  vitro used purified tyrosinase or melanocyte cell lines . in melan - a cells treated with ethanol extract of ginseng seeds , melanin content and
in addition to the crude extract or powder , several studies tested the effects of specific constituents of ginseng . the phenol compounds inhibited tyrosinase activity while ginsenoside prevents uvb - induced intracellular increase of reactive oxygen species [ 4648 ] . in some reports , ginsenosides alone exerted antimelanogenic effects .
aglycone of ginsenoside rh4 inhibited melanin synthesis in b16 melanoma cells , possibly by involvement of protein kinase a pathway .
it significantly reduced melanin content and tyrosinase activity in -msh and forskolin - stimulated b16 melanoma cells .
it reduced the camp level and camp response - element binding protein level in b16 melanoma cells , and this might be responsible for the downregulation of mitf and tyrosinase .
in addition , ginsenoside rb1 inhibited melanogenesis through the inhibition of tyrosinase activity in -msh - stimulated b16 cells in a dose - dependent manner .
the crude methanol extract of the fresh leaves of p.  ginseng showed inhibitory activity on mushroom tyrosinase , and p - coumaric acid was characterized as the principal tyrosinase inhibitor in the extract .
p - coumaric acid inhibited melanogenesis in b16f10 melanoma cells stimulated by -msh , and was suggested to interfere with melanogenesis by its structural similarity with tyrosine .
interestingly , p - coumaric acid showed weaker inhibition against mushroom tyrosinase but more strongly inhibited human or murine tyrosinase in comparison with kojic acid and arbutin .
enzyme kinetics analysis indicate that p - coumaric acid is a mixed type ( for tyrosine ) or competitive inhibitor ( for dopa ) of human tyrosinase .
in addition , p - coumaric acid potently inhibits melanogenesis in human epidermal melanocytes exposed to uvb .
cinnamic acid , one of the major components of cinnamomum cassia blume , is found in the root and seed of p.  ginseng 
 .
cinnamic acid significantly reduced melanin production , tyrosinase activity , and tyrosinase expression in the melan - a cells .
in addition , cinnamic acid showed depigmenting activity on the uvb - tanned skin of brown guinea pigs .
it is already known that the pharmacological actions of these ginsenosides have been closely related to their biotransformation by human intestinal bacteria . although the contents of total ginsenosides in red ginseng and fermented red ginseng using lactobacillus brevis were not significantly different , the ginsenoside metabolite content was higher in fermented red ginseng compared to red ginseng .
the tyrosinase inhibitory activity of fermented red ginseng extract was more potent compared with red ginseng extract in a test using mushroom tyrosinase .
as reviewed above , crude extract or some components of ginseng and its components showed antimelanogenic activities by direct inhibition on key enzymes of melanogenesis , such as tyrosinase .
moreover , ginseng and its components could exert antimelanogenic activity via action on the several factors related in melanocyte physiology . among a large number of soluble factors produced from melanocytes , keratinocytes , fibroblasts , and immune cells in skin , adrenocorticotropic hormone ( acth ) , -msh , endothelin-1 , prostaglandin e2 , prostaglandin f2 , no , and histamine are well - known stimulators of melanogenesis [ 37,5963 ] .
il-1/1 and granulocyte - macrophage colony - stimulating factor ( gm - csf ) stimulate melanogenesis , while il-6 , tgf-1 , and tnf- downregulate melanin production .
gm - csf has been reported to be involved in regulating the proliferation and differentiation of epidermal melanocytes .
treatment of melan - a cells with conditioned media from uv - irradiated sp-1 keratinocytes increased melanocyte proliferation , and the proliferative effect of the conditioned media was blocked by anti - gm - csf antibody treatment . when uv - irradiated sp-1 keratinocytes were treated with red ginseng extract or saponin of red ginseng , the increased melanocyte proliferation by the conditioned media was blocked . in that report ,
red ginseng extract or saponin of red ginseng treatment decreased the expression of gm - csf induced by uv - b irradiation in sp-1 keratinocytes .
as mentioned above , inflammatory cytokines such as il-1 and tnf- take part in the regulation of melanogenesis .
ginseng extracts and ginsenosides have been reported to have anti - inflammatory activities in several different studies .
ginsenosides inhibit different inducer - activated signaling protein kinases and transcription factor nuclear factor ( nf)-b , and then decrease the production of proinflammatory cytokines and mediators of inflammation .
korean red ginseng extracts decreased tnf- and il-8 production in lipopolysaccharide ( lps)-stimulated hacat keratinocytes and show radical scavenging and antioxidant activity in human dermal fibroblasts .
these findings suggest that ginseng extracts and ginsenosides might affect melanogenesis through their anti - inflammatory activities . the effect of ginseng on no production is still questionable .
sun ginseng , a new processed ginseng prepared by steaming at high temperature , reduced uv - b - induced cell damage and decreased no production by inhibition of inducible no synthase mrna synthesis in hacat keratinocytes and human dermal fibroblasts .
red ginseng marc oil inhibited inducible no synthase and cyclooxygenase-2 via nf-b and p38 pathways in lps - stimulated raw264.7 cells .
in addition , ginsenjilinol , a protopanaxatriol - type saponin obtained from the roots of p.  ginseng , shows inhibitory activity on no production in lps - stimulated raw264.7 cells .
by contrast , there are some controversial reports that ginseng extract enhanced no production or no signaling .
hong et  al reported that ginseng extract administration stimulated nongenomic endothelial no synthase activation and enhanced no production in spontaneously hypertensive rats . in another report , water extract of korean red ginseng exerted vasoprotective effects through augmentation of no production by inhibiting arginase .
therefore , the effect of ginseng on melanogenesis via no signaling remains to be clarified by further study .
considerable numbers of immune cells including langerhans cells , macrophages , mast cells , and t cells are working actively in skin tissue . because the immunostimulatory activities of many ginsenosides are known , it is not surprising that ginsenosides could enhance the reactivity of skin immune cells . in a recent paper ,
a cream containing 0.1% ginsenoside f1 ( a metabolite of ginsenoside rg1 ) showed a significant whitening effect on artificially tanned human skin .
however , ginsenoside f1 did not directly inhibit mrna expression of tyrosinase or dct in normal human epidermal melanocytes .
instead , ginsenoside f1 enhanced production of il-13 from human epidermal  t cells , and il-13 significantly reduced the mrna expression and protein amount of both tyrosinase and dct resulting in visible brightening of normal human epidermal melanocyte pellets .
these results suggest that ginsenosides might be able to regulate melanogenesis via their effect on skin immune cells .
recently , several reports have shown that extract , powder , or some constituents of ginseng could inhibit melanogenesis in  vivo or in  vitro
. the underlying mechanisms of the antimelanogenic effect of ginseng or its components included the direct inhibition of key enzymes of melanogenesis ( tyrosinase and dct ) , inhibition of transcription factors ( mitf , nf-b ) or signaling pathways ( protein kinase a pathway and protein kinase c pathway ) involved in melanogenesis , decreasing the production of inducers of melanogenesis ( camp , gm - csf ) , and enhancing production of antimelanogenic factor ( il-13 ) . fig . 
although issues surrounding the antimelanogenic activity of ginseng still remain controversial , especially in its effect on the production of proinflammatory cytokines and no , these recent findings suggest that ginseng and its constituents might be potential candidates for novel skin - whitening agents .
 abnormal changes in skin color induce significant cosmetic problems and affect quality of life . 
 there are two groups of abnormal change in skin color ; hyperpigmentation and hypopigmentation . 
 hyperpigmentation , darkening skin color by excessive pigmentation , is a major concern for asian people with yellow  brown skin . 
 a variety of hypopigmenting agents have been used , but treating the hyperpigmented condition is still challenging and the results are often discouraging . 
 panax ginseng has been used traditionally in eastern asia to treat various diseases , due to its immunomodulatory , neuroprotective , antioxidative , and antitumor activities . recently 
 , several reports have shown that extract , powder , or some constituents of ginseng could inhibit melanogenesis in  vivo or in  vitro . 
 the underlying mechanisms of antimelanogenic properties in ginseng or its components include the direct inhibition of key enzymes of melanogenesis , inhibition of transcription factors or signaling pathways involved in melanogenesis , decreasing production of inducers of melanogenesis , and enhancing production of antimelanogenic factor . 
 although there still remain some controversial issues surrounding the antimelanogenic activity of ginseng , especially in its effect on production of proinflammatory cytokines and nitric oxide , these recent findings suggest that ginseng and its constituents might be potential candidates for novel skin whitening agents . 
Introduction
Effects of ginseng and its components on melanogenesis
Effects of ginseng and its components on factors related to melanogenesis
Conclusion
Conflicts of interest