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The Latest in Whitening Agents

Contact Author Howard I. Maibach, MD; and Michal W.S. Ong
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Skin pigmentation disorders are common, and although they often do not affect consumers physically, many do psychologically.1 Since the discovery in the late 1930s of the depigmenting effects of monobenzyl ether of hydroquinone, a notable number of phenolic compounds have been evaluated as inhibitors of melanin synthesis.2 The most commonly used chemical whitening agents are hydroquinone, arbutin, kojic acid and ascorbic acid, and while most skin whitening agents are deemed effective, hydroquinone is still considered by dermatologists to be one of the most effective.

However, side effects such as burning, itching, crusting, swelling, skin discoloration and ochronosis—a persistent blue-black pigmentation—occur from some depigmenting agents, thus novel and effective solutions are sought. In recent years, new agents, especially from plants, have been discovered (see Potential Whitening Agents sidebar)and extracted to test for their depigmenting effects in vitro and in vivo. This article reviews these most recent skin whitening agents of interest, whose efficacy, mechanism and safety have been tested.3

Tetrapeptide PKEK

Pro-Lys-Glu-Lys (PKEK) has been shown to reduce UVB-induced skin pigmentation in vitro and in vivo. In vitro, it was found to significantly reduce the UVB-induced mRNA expression of interleukin (IL)-6, IL-8, TNF-α, proopiomelanocorticotropin (POMC) and tyrosinase. This was demonstrated in a randomized, double-blinded and vehicle-controlled study on ten healthy volunteers. All volunteers were treated once daily for four consecutive weeks with the two test products on their buttock skin.

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After four weeks, 30 min post-application of the creams, subjects were irradiated with a 1.4 minimum erythema dose (MED) of broadband UVB. Twenty-four hours after irradiation, 4-mm punch biopsies were taken from: the sham-irradiated control area (untreated), a UVB-irradiated skin area (untreated + UVB), a skin area pretreated with the vehicle formulation prior to irradiation (vehicle + UVB), and a skin area pretreated with the formulation containing PKEK prior to irradiation (PKEK + UVB).

PKEK was found to suppress the UVB-induced expression of keratinocyte-derived, pigmentation-inducing mediators (IL-6, IL-8 and α-MSH), as well as melanin synthesis (TYR) and thus skin pigmentation. This was supported by chromametric measurements using a colorimeter, and calculating the factor ITA°.4

PKEK vs. SAP vs. Blend

A double-blinded, vehicle-controlled study of 39 Caucasian women showed significantly faded facial pigment spots after the use of a cream with a PKEK and sodium ascorbyl phosphate (SAP) blend for six weeks, compared with an SAP- or PKEK-only cream. In addition, PKEK was found to enhance the skin whitening potency of an SAP-containing preparation when used by 19 Caucasian subjects for eight weeks on the backs of their hands. According to the intrinsic and extrinsic skin aging score, or SCINEXA, PKEK and SAP-combined formulations reduced skin pigmentation by 26%, compared with 18% by the SAP-only formula.4

Researchers concluded the combination of PKEK and SAP is more efficacious than either alone, and that PKEK also enhances the skin-whitening effect. These findings were supported by another randomized, double-blind, vehicle-controlled study of subjects having skin types V and VI, and with mild acne and melasma. The PKEK-containing formulation was significantly superior to the vehicle at 12 weeks, as far as overall improvement in appearance and evenness of skin tone; these results were statistically significant.

N-Acetyl Glucosamine

N-Acetyl Glucosamine (NAG), an amino hexose found throughout nature and in all human tissues, is known as a precursor to hyaluronic acid. The role of this polymer is to form the extracellular matrix structure in joints and skin, i.e., the dermis and epidermis, and keep them hydrated.5-7 Research has also shown that NAG8 and glucosamine9-11 are able to reduce the production of melanin in human cell cultures by inhibiting the glycosylation of tyrosinase to prevent activation of this enzyme, in turn reducing melanin formation.

NAG + Niacinamide

Clinical tests also have demonstrated that NAG is able to reduce skin hyperpigmentation;12, 13 however, combined treatments of NAG and niacinamide were found to be more effective than NAG alone.14, 15 Specifically, one randomized, double-blind, vehicle-controlled, split face study showed that combining 2% NAG with 4% niacinamide reduced hyperpigmentation more than NAG only.14

Similarly, a 10-week, randomized, double-blind, vehicle-controlled, full face, parallel-group study compared a daily regimen of either a morning SPF 15 sunscreen moisturizing lotion with an evening moisturizing cream, each containing 2% NAG and 4% niacinamide test formulations (n = 101); or the SPF 15 lotion and cream vehicles only as controls (n = 101). The combined test formulation regime with NAG and niacinamide was significantly (p < 0.05) more effective than the vehicle control regime in reducing detectable facial spots and pigmentation. Overall, both regimens were well-tolerated; only seven (3.5%) of the 202 subjects reported adverse effects. Two subjects from each group reported moderate skin irritation and withdrew from the study. Two subjects from the test formulation regime group and one subject from the vehicle group experienced mild irritation but did not withdraw.15

Orchid vs. 3% Vitamin C

Orchid extract also has been reported to have skin whitening effects. Forty-eight Japanese female volunteers, ages 30 to 60, were recruited in a randomized, controlled, split-face study. They applied Formulation A, containing 5% orchid extract and smoothing and rejuvenating ingredients, to one side of their face and Formulation B, containing 3% vitamin C derivative, to the other side. The efficacy of each formula was assessed objectively using colorimetry, and subjectively using questionnaires and clinical evaluations by dermatologists. Good agreement was found between the results of the clinical evaluations and dermatologists: orchid extract had similar efficacy to vitamin C against melasma and lentigo senilis.16 Note that batch to batch reproducibility was not reported.

Artocarpus Family

Artocarpus is a genus of about 60 trees and shrubs belonging to the mulberry family, Moraceae. It is commonly found in Southeast Asian and Pacific origin. Artocarpus incisus (AI)17 and Artocarpus lakoocha (AL)18 were discovered as potential whitening agents, as researchers showed that AI inhibited tyrosinase activity equal to kojic acid, and inhibited melanin biosynthesis of both cultured B16 melanoma cells without cytotoxicity.17 Depigmenting effects also were found in tests on the backs of brown guinea pigs having UVB-induced hyperpigmentation, without inducing skin irritation.17

In relation, Sritularak et al.19 found that AL exhibited high anti-tyrosinase activity, and that due to the polyphenolic nature of its active constituent, oxyresveratrol, it may also have antioxidative properties.20 Note that batch reproducibility was not reported.

Efficacy, Safety of AL

In a parallel clinical trial comparing AL-containing formulas with others combining 3% kojic acid and 0.25% licorice extract, the AL formulations imparted the most significant effects the fastest—i.e., after just four weeks of application. The kojic acid and licorice formulas required six weeks before significant whitening effects were observed (p < 0.05). The rate of improvement was dependent upon the type of formulation and area of application. Specifically, an o/w emulsion gave better lightening activity than a propylene glycol-based solution. Since only 0.10–0.25% concentrations of AL were required for efficacy, this extract has potential as a safe, effective and economical skin whitening agent for the cosmetics industry.18

Morus alba Extract

Mulberry extract contains flavonoids and exhibits antioxidant properties.21 Similar to other whitening agents, mulberry extract inhibits tyrosinase activity competitively, comparable to hydroquinone and kojic acid;22 however, it does not suppress tyrosinase synthesis or gene expression.23-28 In one brown guinea pig model wherein the animals had UV-induced hyperpigmentation, a decrease in melanin production was observed with Ramulus mori (young twigs of Morus alba L.) extract. R. mori was extracted with a mixture of ethyl alcohol and water (EtOH : H2O = 70:30) and dried to powder. This powder was dissolved in 1,3 butylene glycol. Acute toxicity, skin irritation, eye irritation, skin sensitization and acute oral toxicity26 were not observed in the test animals.

Efficacy, Safety of Mulberry

Fifty patients with melasma were recruited for a randomized, single blind, placebo-controlled trial. Twenty-five patients were treated with 75% mulberry extract oil; another 25, with a placebo. The efficacy of the oil was assessed using the melasma area and severity index (MASI score), a mexameter reading and the melasma quality of life score (MelasQOL). The mulberry extract oil gave significant improvement, compared with the placebo. The mean MASI score improved from 4.076 at baseline to 2.884 at week eight, post-treatment. The placebo group showed almost no improvement, measuring 3.383 at baseline and 3.392 at week eight.

Mexameter readings also demonstrated reductions in hyperpigmentation with the oil treatment; readings dropped from 355.56 at baseline to 312.52 at week eight. The placebo group showed an increase in mexameter readings, from 368.24 to 372.12 at week eight. Lastly, the MelasQOL score of patients post-mulberry extract treatment improved from 58.84 at baseline to 44.16 at week eight. The placebo group showed significantly less improvement—from 57.44 at baseline to 54.28 at week eight.

Regarding its safety profile, the 75% mulberry extract oil caused only mild itching in four patients; interestingly, 12 patients in the placebo group reported either itching or erythema.29 Mulberry extract is thus considered a safe whitening skin agent. Also, no toxicity was found with a human skin irritation test.26 Note that result reproducibility from different batches was not reported.


Taken together, many populations desire more effective preparations for lightening and/or depigmenting skin, and today’s methodologies, skillfully utilized by efficient research and development teams, should permit significant and cost-effective means of meeting those needs. The consumer/patient awaits such products with enhanced skin lightening efficacy as well as documented safety.

Send e-mail to michalong@gmail.com.
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14. DL Bissett et al, Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine, J Cosmet Dermatol 6(1) 20–6 (Mar 2007)
15. AB Kimball AB et al, Reduction in the appearance of facial hyperpigmentation after use of moisturizers with a combination of topical niacinamide and N-acetyl glucosamine: Results of a randomized, double-blind, vehicle-controlled trial, Br J Dermatol 162(2) 435–41 (Feb 1, 2010)
16. T Tadokoro et al, Whitening efficacy of plant extracts including orchid extracts on Japanese female skin with melasma and lentigo senilis, J Dermatol 37(6) 522–30 (2010)
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20. K Wachiranuntasin, Evaluation of Stability, antioxidative and free radical scavenging activities of Artocarpus lakoocha heartwood extract, Chulalongkorn University, Bangkok (2005) p 198
21. W Zhu and J Gao, The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders, J Invest Derm Symp Proc 13(1) 20–4 (Apr 2008)
22. S Badreshia-Bansal and ZD Draelos ZD, Insight into skin lightening cosmeceuticals for women of color, J Drugs Derm (2007)
23. S Nattapong and L Omboon, A new source of whitening agent from a Thai mulberry plant and its betulinic acid quantitation, Nat Prod Res 15 22(9) 727–34 (Jun 2008)
24. N Pianwijanpong, N Pongpan, L Suntornsuk and O Luanratana, The triterpene constituents of the root bark of a hybrid between Morus alba L. and M-rotundiloba koidz. and its antityrosinase activities, Nat Prod Commun 2(4) 381–4 (2007)
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Potential Whitening Agents

potential whitening agents

In recent years, new agents, especially from plants, have been discovered (see Potential Whitening Agents sidebar)and extracted to test for their depigmenting effects in vitro and in vivo.

Biography: Howard I. Maibach, MD, University of California, San Francisco

Howard I. Maibach, MD, is a professor of derma­tology at the University of California School of Medicine, San Francisco. His labor­atory has been interested in and has published exten­sively on derm­ato­pharma­cology and dermatotoxicology.

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