Skin Lightening (whitening) in herbs, Foods and Antioxidants Points of View

 Kyle J. Norton(Draft Article)

Human skin pigmentation is the result of natural selection evolved to prevent damage to skin through regulation of ultraviolet radiated penetration depending to the production of melanin in the skin cells.
1. Hypo-pigment
a. Vitiligo is defined as a condition of destruction of cells that give your skin its color, causing white patches on your skin.
b. Albinism is a congenital disorder causes of complete or partial absence of pigment in the skin, hair and eyes duas a result of restriction of the skin cells from producing melanin
2.Hyper pigment is a result of over production of pigments of certain cells in the skin, causing skin darkening in some area, such as tan or brown patches, commonly on the facial skin
3. Skin discoloring is a result of discoloring your skin in specific spots or very widespread
4. Chloasma is the appearance of brown patches of pigmentation on the forehead, cheeks, and neck
due to hormonal change during pregnancy.
5. Melasma happens to women who have fluctuation of hormones, are taking birth control pills and certain medications. with brownish-grayish patches on the skin, most often on the cheek.
Epidemiological studies, linking herbal medicine in skin lighting may have produced certain interest results(a)(b)(c).
A. The herbs
1. Ampelopsis japonica (Bai Lian)
Bai Lian is also known as Japanese Ampelopsis Root, the bitter, sweet, acrid and cool herb has been used in TCM to redice infection and to treat carbuncles, sores, scalding injuries, dysentery with blood, intestine pain, hemorrhoids as it clears Heat, expels toxins, resolves ulcers, promotes muscle regeneration, etc, by promoting the function of liver channel.
Ampelopsis japonica  may process the property in treating skin hyperpigmentation disorders, such as melisma. According to the study at the Macao Polytechnic Institute,  Linderagalactone c and (+)-n-methyllaurotetanine found in  Ampelopsis japonica  exhibited the strongest prospects in topical formulations, throguh high predicted tyrosinase binding scores and displayed good skin permeation properties in Surflex-Dock and the QSAR-based Dermal Permeability Coefficient Program (DERMWIN) and Skin Irritation Corrosion Rules Estimation Tool (SICRET) implemented in Toxtree.(1). The screening of 50 extracts from traditional Chinese medicines (TCM) used for tyrosinase activity-inhibiting agents, Ampelopsis japonica showed similar or greater ratio of cell growth IC(50) to cellular tyrosinase IC(50) when compared with other herbs(2).

2. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgo biloba, one of the potent herb showed more advanced binding energies than the gold standard whitening agents, arbutin and kojic acid(1). Glycol extracts of ginkgo boiloba(F1A+M), may process of arbutin diffusion from the produced hydrogel formulations. According to Uniwersytet Medyczny w Łodzi, formulation containing glycol extract of ginkgo processed the most effective in arbutin release to the acceptor fluid through a semipermeable membrane (3). Other herbal extracts were also found to have a similar effect in promoting the process of arbutin release, including rosemary, sage and nettle(4).

3. Spicebush Root (Wu Yao)
Wu Yao is also known as Spicebush Root. The acrid and warm herb has been used in TCM  as   increased metabolism, antibiotic, anti-viral agent andto harmonize peristalsis of digestive tract, release intestinal gas, etc., as it moves Qi, warms the Kidneys. calms pain, etc. by enhancing the functions of lung, spleen, kidney and bladder.channels.
The study at Macao Polytechnic Institute, in the finding of herbal medicine used as tyrosinase inhibitors and for treatment of skin hyperpigmentation disorders, showed a promising result of
Spicebush Root's chemical constituents in tyrosinase binding scores and displayed good skin permeation properties and minimal potential for skin sensitization and irritation(5). Other study at the Institute of Chinese Materia Medica of Shanghai University of Traditional Chinese Medicine, found that Spicebush Root consists appreciable antityrosinase activity with more than 50% inhibition against mushroom tyrosinase activity(6).

4. Chinese gall (Wu Bei zi)
Wu Bei Zi is also known as Chinese Gall. The  sour, tart and cold herb has been used in TCM to treat chronic cough, chronic diarrhea with or without infection, spermatorrhea, night sweating, bleeding not during menses, etc., as it restrains Lungs, moves Fire downwards, strengthens the Intestines andthe Essence, prevents sweating, stops bleeding, etc. by enhancing the functions of lung, large intestine and kidney channels.
Chinese gall extract in the testing against mushroom tyrosinase activity inhibition, using ultraviolet A (UVA) or alpha-melanocyte-stimulating hormone (alpha-MSH) to stimulate B16 cells showed a promising effect in inhibition of melanin biosynthesis associated with hyperpigmentation in a dose-dependent manner, according to National Chiayi University(7). In Mouse melanocyte cell lines, water extract of Galla Chinensis, showed to exhibit higher depigmentation activity and caused lower tyrosinase activity(8).

5. Sargassum polycystum(Brown seaweed)
Sargassum polycystum, a type of brown seaweed, has been used for the treatment of skin-related disorders in traditional medicine. The ethanolic crude extract from Sargassum polycystum showed significant inhibition of melanogenesis through down activated cellular tyrosinase activity in B16F10 cells(9).

6. Nardostachys chinensis(Gan Song)
gan Song also known as Nardostachyos Root and Rhizome. The herb has been used in traditional Chinese medicine to treat melasma and lentigines, move Qi, calm pain, eliminate stagnation and invigorates the Spleen. According to Pusan National University, the active 20% methanol chromatographic fraction from the ethyl acetate layer (PPNC) showed to suppressed the melanin synthesis s, through stimulated MEK/ERK phosphorylation and PI3K/Akt signaling with suppressing cAMP levels and subsequently stimulating MITF and TRPs down-regulation(10).

7. Cuscuta japonica(Tu Si Zi)
Tu Si Zi is also known as Dodder Seed. The acrid, sweet and  neutral herb has been used in TCM to treat  psychological disorder, calm the fetus, prevent miscarriage, etc. as it tonifies kidneys, liver and spleen, improves yin, etc. by enhancing the functions of liver and kidney channels.
According to Pusan National University, the aqueous fraction from Semen cuscutae (AFSC) showed a marked reduction of melanin synthesis and tyrosinase activity in α-MSH-stimulated B16F10 cells through inhibited p38 MAPK phosphorylation with suppressed cAMP levels and subsequently down-regulate MITF and TRP expression(11).

8. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin, a major chemical constituents of turmeric, showed to suppressed alpha-MSH-stimulated melanogenesis probably through involved the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt(12). Other sudy conducted by Pusan National University, also showed partial purification from C. longa (PPC)  reduced melanin synthesis via MITF and its downstream signal pathway including tyrosinase and TRPs in alpha-MSH-induced melanogenesis, through activation of the MEK/ERK or Akt(13).

9. Fermenting red ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng(RG), wild ginseng, American ginseng (root).
Fermented red ginseng (FRG), increased contents of ginsenoside metabolites, such as Rg3, Rg5, Rk1, compound K, Rh1, F2, Rg2, and flavonoids content showed to increased anti-wrinkle efficacy, whitening efficacy, and reduced toxicological potency compared to RG(13a)

B. The foods
1. Long Yan (Longan)
Long Yan is also known as longan. The slightly sweet and neutral herb (fruit) has been used in TCM as notification after illnesses, neurasthenia, forgetfulness, palpitation, insomnia, etc. as it tonifies Heart and Spleen, benefits Qi and Blood, etc. Longan seeds containing high levels of  polyphenolic compounds such as corilagin, gallic acid and ellagic acid, may be potential sources of potent natural dietary antioxidants in the application as a new natural skin-whitening agent(14), through its higher antioxidant and antityrosinase activities(15).

2. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Green tea polyphenol may be used as a natural ingredient with excellent physiological functions for the human skin through cosmetic or food composition(16). Other study of the effects of tea polysaccharides (TPS) and polyphenols (TPP) on skin, showed to exhibit the moisture absorption and retention, sunscreen, promoting the proliferation of fibroblast cells, and tyrosinase inhibitory effect(17).

3. Cinnamon
Cinnamon is a spice derived from the inner bark of tree, native to South East Asia, of over 300 species of the genus Cinnamomum, belonging to the family Lauraceae.. The herb has been use in herbal and traditional medicine as anti-fungal and bacteria level to improve reproductive organ, prevent flatulence and intestinal cramping, treat indigestion, diarrhea, bad breath, headache, migraine, etc.
The essential oil extracted from Cinnamomum cassia Presl (CC-EO) and its major component, cinnamaldehyde, possess potent anti-tyrosinase and anti-melanogenic activities through theirs antioxidant activities and  may be a potential source of skin-whitening agents(18)

4. Red Onion((Allium cepa)
The onion is a plants in the genus Allium, belongs to the family Alliaceae, a close relation of garlic. It It is often called the "king of vegetables" because of its pungent taste and found in a large number of recipes and preparations spanning almost the totality of the world's cultures. Depending on the variety, an onion can be sharp, spicy, tangy, pungent, mild or sweet.
Quercetin 4'-O-β-D-glucopyranoside was isolated from the dried skin of A. cepa. showed tyrosinase inhibitory activity as it possesses ingredients with potential for skin-whitening cosmetics(19).

5. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
[6]-Gingerol, an active component of ginger not only (25-100 µM) effectively suppressed murine tyrosinase activity and decreases the amount of melanin, but also decreased the intracellular reactive oxygen species (ROS) level in a dose-dependent manner(20). the University of Malaya, in the study of the effects of [8]-Gingerol, another active component of Zinger, found that  [8]-gingerol (5-100μM) not only effectively suppressed intracellular tyrosinase activity and decreased the amount of melanin in B16F10 and B16F1 cells, but also fectively decreased intracellular reactive species (RS) and reactive oxygen species (ROS) levels at the same dose manner, probably through down-regulation of both mitogen-activated protein kinases (MAPK) and protein kinase A (PKA) signaling pathways or through its antioxidant properties(21).

6.  Pomegranate
Pomegranates is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
Pomegranate extract (PE) containing 90% ellagic acid administered orally, inhibited UV-induced skin pigmentation on the back of brownish guinea pigs with  skin-whitening effect was similar between guinea pigs fed with PE and those fed with L-ascorbic acid(21a) and moderate effect in human skin(21b).

C. The Antioxidants
C.1. Free radical scavengers
Suggestions of antioxidants, may be next potential agent in inhibition of tyrosinase activity and reduction of the melanin content in cells(22)(22a)
1. Vitamin C,
Vitamin C also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.
Ascorbic acid (AA) has been well known as a skin whitening agent, according to the Mahidol University, AA showed to inhibit UVA-mediated catalase (CAT) inactivation, glutathione (GSH) depletion, oxidant formation and NO production through suppression of eNOS and iNOS mRNA via its antioxidant defense(23). In the comparison of orchid extracts and 3% vitamin C derivative formulated, researchers at the Osaka National Hospital, National Hospital Organizationfound that the orchid-rich plant extracts possess efficacy similar to vitamin C derivative in whitening the skin as well as melasma and lentigo senilis on the face of Japanese women(24). Other study suggested that topical application of the composition of L(+) lactic acid supplemented with ascorbic acid (1%) produced a whitening effect and a modest preferential lightening of age spots which becomes apparent after three months, through demonstrated clinically by the test panelists, and trained clinicians, and with objective instrumental methods(25).

2. Vitamin E
Vitamin E,  a fat soluble vitamin, consisting eight different variants (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) with varying levels of biological activity(26), found abundantly in corn oil, soybean oil, margarine, wheat germ oil, sunflower,safflower oils, etc. plays an important role in neurological functions and inhibition of platelet aggregation, regulation of enzymatic activity, free radical scavenger, etc..
The study in comparison of the effects of vitamin E analogues (d-alpha-, dl-alpha-, d-beta-, d-gamma-, and d-delta-tocopherols, d-alpha- and dl-alpha-tocopheryl acetates) and 2,2,5,7,8-pentamethyl-6-hydroxychroman (PMC) on melanogenesis in mouse B16 melanoma cells, showed a positive effects of d-beta-tocopherol and d-gamma-tocopherol, 2 variants of vitamin E, in skin whitening with lower skin toxicity, as well as improved skin pigmentation such as skin spots and freckles caused by UV exposure(27). According to Kobe University School of Medicine, alpha-Tocopheryl ferulate (alpha-TF), a compound containing alpha-T (a variant of vitamin E) and ferulic acid exhibited an efficient whitening effects, through suppressed melanogenesis and inhibited biological reactions induced by reactive oxygen species(28)(29).

C.2. The antioxidants
1. Resveratrol
Resveratrol is a phytochemical in the class of Stilbenoids, found abundantly in skins and seed of grape wine, nuts, peanuts, etc.
Piceatannol, a derivative of resveratrol exerted its antimelanogenic action through the combined effect of antioxidative property
and suppressed RS generation while increasing the GSH/GSSG ratio(30). According to ¹Johnson &
Johnson Skin Research Center, resveratrol may be a potential cosmetic skin whitening agent through
reduced microphthalmia-associated transcription factor and tyrosinase promoter activities(31).

4. Glutathione
Glutathione (GSH), an antioxidants plays an important role in protecting cells against the free radicals
and ixidative stress, may be a potential agent in the management of hyperpigmentation(32). According
to the Chulalongkorn University, orally administered glutathione, 500 mg per day for 4 weeks, was found
effectively in reduced melanin indices consistently in all subjects(33) and may be used in the treatment
of pigmentary disorders.(34). Other study also indicated the effectiveness of  glutathione in regulatesing
 melanocytotoxicity and depigmenting potency of N-acetyl-4-S-CAP in black and yellow mice(35)


Taken altogether, although with scattered data, the herbs, foods, and antioxidants indicated above may potent in exhibition of the depigment and lightening (whitening) effects, through inhibited, and biological reactions induced by reactive oxygen species and suppressed melanogenesis and intracellular tyrosinase activity. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.

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References
(a) Tyrosinase modulation by five Rwandese herbal medicines traditionally used for skin treatment by Kamagaju L¹, Morandini R, Bizuru E, Nyetera P, Nduwayezu JB, Stévigny C, Ghanem G, Duez P.(PubMed)
(b) An ethnobotanical survey of medicinal plants used in Rwanda for voluntary depigmentation by Kamagaju L¹, Bizuru E, Minani V, Morandini R, Stévigny C, Ghanem G, Duez P.(PubMed)
(c) Tyrosinase inhibition by extracts and constituents of Sideroxylon inerme L. stem bark, used in South Africa for skin lightening by Momtaz S¹, Mapunya BM, Houghton PJ, Edgerly C, Hussein A, Naidoo S, Lall N.(PubMed))
(1) In silico prediction of the cosmetic whitening effects of naturally occurring lead compounds by Fong P¹, Tong HH.(PubMed)
(2) Screening of Chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells by Ye Y¹, Chou GX, Mu DD, Wang H, Chu JH, Leung AK, Fong WF, Yu ZL(PubMed)
(3) [Glycol plant extracts in the prescription of topical skin-whitening hydrogels].[Article in Polish] by Piechota-Urbańska M¹, Berner-Strzelczyk A.(PubMed)
(4) [The effect of dry standardized plant extracts on the process of arbutin release from topical preparations produced on Carbopol base].[Article in Polish] by Piechota-Urbańska M.(PubMed)
(5) In silico prediction of the cosmetic whitening effects of naturally occurring lead compounds by Fong P¹, Tong HH.(PubMed)
(6) Screening of Chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells by Ye Y¹, Chou GX, Mu DD, Wang H, Chu JH, Leung AK, Fong WF, Yu ZL.(PubMed)
(7) Melanogenesis inhibition by gallotannins from Chinese galls in B16 mouse melanoma cells by Chen LG¹, Chang WL, Lee CJ, Lee LT, Shih CM, Wang CC.(PubMed)
(8) Depigmentation of melanocytes by the treatment of extracts from traditional Chinese herbs: a cell culture assay by Zhong S¹, Wu Y, Soo-Mi A, Zhao J, Wang K, Yang S, Jae-Ho Y, Zhu X.(PubMed)
(9) Inhibitory effects of Sargassum polycystum on tyrosinase activity and melanin formation in B16F10 murine melanoma cells by Chan YY¹, Kim KH, Cheah SH(PubMed)
(10) Partially purified components of Nardostachys chinensis suppress melanin synthesis through ERK and Akt signaling pathway with cAMP down-regulation in B16F10 cells by Jang JY¹, Kim HN, Kim YR, Choi WY, Choi YH, Shin HK, Choi BT.(PubMed)
(11) Aqueous fraction from Cuscuta japonica seed suppresses melanin synthesis through inhibition of the p38 mitogen-activated protein kinase signaling pathway in B16F10 cells by Jang JY¹, Kim HN, Kim YR, Choi YH, Kim BW, Shin HK, Choi BT.(PubMed)
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(15) Enhanced antioxidant and antityrosinase activities of longan fruit pericarp by ultra-high-pressure-assisted extraction by rasad KN¹, Yang B, Shi J, Yu C, Zhao M, Xue S, Jiang Y.(PubMed)
(16) Physiological activity of irradiated green tea polyphenol on the human skin by An BJ¹, Kwak JH, Son JH, Park JM, Lee JY, Park TS, Kim SY, Kim YS, Jo C, Byun MW.(PubMed)
(17) Protective effects of tea polysaccharides and polyphenols on skin by Wei X¹, Liu Y, Xiao J, Wang Y.(PubMed)
(18) Cinnamomum cassia essential oil inhibits α-MSH-induced melanin production and oxidative stress in murine B16 melanoma cells by Chou ST¹, Chang WL, Chang CT, Hsu SL, Lin YC, Shih Y.(PubMed)
(19) Tyrosinase inhibitory effect of quercetin 4'-O-β-D-glucopyranoside from dried skin of red onion (Allium cepa) by Arung ET¹, Wijaya Kusuma I, Shimizu K, Kondo R.(PubMed)
(20) Inhibitory effect of [6]-gingerol on melanogenesis in B16F10 melanoma cells and a possible mechanism of action by Huang HC¹, Chiu SH, Chang TM.(PubMed)
(21) [8]-Gingerol inhibits melanogenesis in murine melanoma cells through down-regulation of the MAPK and PKA signal pathways by Huang HC¹, Chou YC, Wu CY, Chang TM.(PubMed)
(21a) Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation by Yoshimura M¹, Watanabe Y, Kasai K, Yamakoshi J, Koga T.(PubMed)
(21b) Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin by Kasai K¹, Yoshimura M, Koga T, Arii M, Kawasaki S.(PubMed)
(22) Biofunctional Constituents from Liriodendron tulipifera with Antioxidants and Anti-Melanogenic Properties by Li WJ¹, Lin YC, Wu PF, Wen ZH, Liu PL, Chen CY, Wang HM.(PubMed)
(22a) The effects of areca catechu L extract on anti-inflammation and anti-melanogenesis by Lee KK¹, Choi JD.(PubMed)
(23) Inhibition of UVA-mediated melanogenesis by ascorbic acid through modulation of antioxidant defense and nitric oxide system by Panich U¹, Tangsupa-a-nan V, Onkoksoong T, Kongtaphan K, Kasetsinsombat K, Akarasereenont P, Wongkajornsilp A.(PubMed)
(24) \Whitening efficacy of plant extracts including orchid extracts on Japanese female skin with melasma and lentigo senilis by Tadokoro T¹, Bonté F, Archambault JC, Cauchard JH, Neveu M, Ozawa K, Noguchi F, Ikeda A, Nagamatsu M, Shinn S.(PubMed)
(25) The effects of topical l(+) lactic Acid and ascorbic Acid on skin whitening by Smith WP.(PubMed)
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(28) The depigmenting effect of alpha-tocopheryl ferulate on human melanoma cells by Funasaka Y¹, Chakraborty AK, Komoto M, Ohashi A, Ichihashi M.(PubMed)
(29) Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes by Funasaka Y¹, Komoto M, Ichihashi M.(PubMed)
(30) Piceatannol inhibits melanogenesis by its antioxidative actions by Yokozawa T¹, Kim YJ.(PubMed)
(31) Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation by Lin CB¹, Babiarz L, Liebel F, Roydon Price E, Kizoulis M, Gendimenico GJ, Fisher DE, Seiberg M.(PubMed)
(32) Natural ingredients for darker skin types: growing options for hyperpigmentation by Alexis AF Blackcloud P.(PubMed)
(33) Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study by Arjinpathana N¹, Asawanonda P.(PubMed)
(34) Glutathione as a depigmenting agent: an overview by Villarama CD¹, Maibach HI.(PubMed)
(35) Glutathione plays a key role in the depigmenting and melanocytotoxic action of N-acetyl-4-S-cysteaminylphenol in black and yellow hair follicles by Alena F¹, Dixon W, Thomas P, Jimbow K.(PubMed)