INTRODUCTION:

Ranging from white to brown to black, the colour of human skin is attributed to melanin, a chemically inert and stable major pigment found in mammalian skin. Melanin is synthesized by melanocytes scattered throughout the stratum basale of epidermis via melanogenesis. Melanocytes then transfer the melanin contained in the cellular organelle melanosomes to the neighbouring keratinocytes. Type and amount of melanin synthesized by melanocytes as well as uptake by keratinocytes determine the extent of skin colouration^1-4.

Increased melanin synthesis protects against UV irradiation, photo-carcinogenesis and oxidative stress. Both intrinsic and extrinsic factors are responsible for the regulation of melanogenesis. Genetic, hormonal environment as well as inflammation and the associated molecules secreted by keratocytes, fibroblasts, inflammatory cells and endocrine cells can be categorized as intrinsic factors whereas ultraviolet radiation, chemical products and environmental pollutants are the extrinsic factors associated with increased melanogenesis. The skin response to these factors is regulated by the cutaneous neuroendocrine system^5,6.

Although melanogenesis provides protection against the destructive effects of UV radiation, excessive production of melanin is associated with skin disorders such as melasma, acanthosis nigricans, lentigines and periorbital hyperpigmentation¹. Generally, hyperpigmentation disorders are difficult to treat and the use of skin lightening agents are essential⁷. Depending on the location of melanin deposition, hyperpigmentation manifests as brown discolouration when melanin deposits in the epidermis while blue discolouration is observed for the deposition of melanin in the dermis⁸. Being one of the most prevalent dermatologic disorders, hyperpigmentation may have a significant impact on the psychosocial aspect of an individual⁹.

Hydroquinone, a phenolic chemical is the current gold standard for the treatment of hyperpigmentation². The early literature on the depigmentation effect of hydroquinone was first reported in 1936¹⁰ in which the feeding of 30 mg/kg/day of hydroquinone to black haired cats for six to eight weeks have resulted in the lightening of the hair colour, confirmed by another study by Martin and Ansbacher that the feeding of hydroquinone for four to twenty weeks has contributed to the development of achromatrichia in young mice¹¹. However, hydroquinone is associated with several adverse effects such as skin irritation, contact dermatitis, mutagenic to mammalian cells and cytotoxic to melanocytes². Besides, darker-complexioned individuals may also develop exogenous ochronosis due to the use of hydroquinone for skin-bleaching¹². The European Union has banned the use of hydroquinone in cosmetics since January 2001 while a statement has been released by the US Food and Drug Administration (FDA) in August 2006 for the consideration of all skin-bleaching products as new drugs requiring new drug application to be marketed. Decision was made due to the most recent safety data of prolonged hydroquinone use which have been associated with side effects such as neuropathy, exogenous ochronosis, leukoderma with confetti-like depigmentation¹³. Hence, there is a need for the search of a potent agent with little or less severe side effects^7,14. Plants have been used to treat various ailments for millennia and the use of plants is often perceived to be milder, safer and healthier, in addition to being the more affordable option, rendering the botanicals as increasingly popular alternatives to the standard agents. Besides, studies have shown that the phytochemicals possess a multitude of cellular actions which can be used to treat various skin disorders¹⁵.

This review summarizes the use of botanically derived agents, either in the form of plant extracts or isolated bioactive compounds in the management of hyperpigmentation disorders.

METHODOLOGY:

In June 2020, a systematic literature search using the database of PubMed had been performed to identify the relevant studies to be included in the review. The key terms used for the searches include plants, phytochemicals, hyperpigmentation, anti-tyrosinase, tyrosinase inhibitors and skin-whitening. Boolean operators such as “AND” and “OR” were used to generate more focused search results and the articles screened range from 2010 till 2020. Only clinical studies involving botanically-derived compounds and pigmentation were included in the review. The searches were filtered and of the 33 articles, 9 studies met the inclusion criteria. The flow of the searches is shown in Fig. 1. The studies are summarized in Table 1. Among the studies included in the review, some of the phytochemicals were not studied independently, despite, they were examined in combination, either in the form of extracts or formulated with other compounds or combined with other therapies.

Fig. 1: Flow diagram of searches and assessment of the studies included in the review

Mechanisms of Action in the Treatment of Hyperpigmentation:

Depigmentation involves several mechanisms of action. Since the excessive deposition of melanin leads to areas of increased pigment density or unusual dispersion of pigment, inhibition of melanogenesis or dispersion of melanin at any stage may affect the clinical manifestation of hyperpigmentation⁹.

Melanocyte-specific enzymes like tyrosinase, tyrosinase-related protein 1 (TYRP1) and tyrosinase-related protein 2 (TYRP2) play a vital role in melanogenesis³. Tyrosinase, the key enzyme involved in the critical rate-limiting steps is a copper-containing metalloenzyme with binuclear copper ions and it catalyzes two primary reactions in melanin synthesis: (i) hydroxylation of monophenols to o-diphenols; (ii) oxidation of o-diphenols to o-quinones. The subsequent modification of melanin is then performed by other enzymes such as TYRP1 and DOPAchrome tautomerase (DCT)^2,3.

Tyrosinase inhibitors which control the activity of tyrosinase have been applied in medical and cosmetic products as anti-melanoma and skin whitening agents¹. Hydroquinone, retinoids, kojic acid and azelaic acid are the well-known depigmenting agents which possess anti-tyrosinase activities⁹. Phytochemicals such as aleosin, arbutin and bakuchiol also inhibit the activity of tyrosinase enzyme for their depigmenting effects.

Inflammatory mediators like leukotrienes C4 and D4 and prostaglandin E2 have shown to enhance melanogenesis by stimulating the growth of melanocyte cells and proliferation of dendrite. Other inflammatory mediators such as interleukin-1, interleukin-6 and reactive oxygen species stimulate the melanocytes to synthesize melanin^9,16. Besides, melanocyte cell damage caused by inflammation also results in the aberrant transfer of melanosomes to the dermis which manifests as hyperpigmentation¹⁷. Hence, hyperpigmentation may be inhibited by phytochemicals such as vitamin E, bakuchiol and flavonoids which possess anti-inflammatory and antioxidant properties. Flavonoids are potent antioxidant which present in few plant extracts and they suppress melanin synthesis through the inhibition of reactive oxygen species⁹.

Furthermore, stimulation of keratinocyte cell turnover and subsequent promotion of melanin loss through epidermopoiesis by retinoids is another depigmenting mechanism¹⁵. Alpha-bisabolol and bakuchiol also inhibit melanogenesis induced by α-melanocyte-stimulating hormone (MSH).

Plants and Bioactive Constituents for Pigmentation Control:

A. Plants:

1. Aloe vera:

Belonging to the Liliaceae (Asphodelaceae) family, Aloe vera which contains various minerals, vitamins and amino acids has been gaining increasing attention for its application in some dermatological disorders. In vitro studies have shown that aleosin derived from Aloe vera possesses tyrosinase inhibitory activity which makes Aloe vera a potential depigmenting agent in the management of melasma during pregnancy¹⁸. In a clinical study conducted by Ghafarzadeh and Eatemadi¹⁹, the fresh Aloe vera plant was obtained from Iran, the leaves were cut vertically followed by extraction of the gel. Both test group (n=90) receiving liposomal-Aloe vera leaf gel extract (AGE) and the control group (n=90) of AGE have shown improvement in the Melasma Area and Severity Index (MASI) after 5 weeks of treatment in which more noticeable results were observed for the test group. Although the study’s objective was oriented to investigate the effectiveness of liposomal delivery system and no placebo control group was available, hypopigmentation effect of Aloe vera has been observed, proving the efficacy of Aloe vera in treating hyperpigmentation disorders irrespective of the delivery systems used¹⁹. In addition to the previous evidence from the studies conducted which supported the pigmentation suppression effects by Aloe vera, the authors suggested that Aloe vera could be an alternative for the management of melasma¹⁹.

2. China camellia, Portulaca oleracea, sanchi and Prinsepia utilis herbal mixture:

A herbal mixture of China camellia (1%), Portulaca oleracea (1%), sanchi (0.5%) and Prinsepia utilis oil (0.5%) targeting the four different pathogeneses of melasma was examined by Zhang et al (N=90). The herbal ingredients used were obtained from West China, Kunming Institute of Botany, Chinese Academy of Sciences. The cream was then manufactured by Beitaini Biotechnological Co., Ltd. (China) using the herbal ingredients in the concentrations aforementioned. Improvement of melasma results from the inhibition of tyrosinase and melanogenesis by China camellia, anti-inflammatory and anti-allergy properties of Portulaca oleracea, promotion of microcirculation by sanchi, as well as improved skin barrier function by Prinsepia utilis²⁰. After the application of the creams twice daily for 12 weeks, the arbutin cream and the test cream containing the herbal mixture have shown improved MASI scores and average melanin index but the test cream was superior to the arbutin cream in both assessments in addition to the lowered erythema index which was not observed in patients using the arbutin cream. Besides, safety testing performed also showed a marked reduction in the density of inflammatory cells with the test cream compared to the two control groups²⁰. Mild erythema and itching were experienced by patients using the arbutin cream but not with those who used the test cream. The efficacy and safety of the cream containing the herbal mixture in the treatment of melasma were proven but more clinical studies are needed to warrant its use²⁰.

3. Petroselinum crispum:

The brewed leaves and stems of Petroselinum crispum (Iranian parsley purchased from the market was used) have been reported to demonstrate facial spot removal and skin whitening effects which may be attributed to vitamin C and flavonoids²¹. Both vitamin C and flavonoids are antioxidants which may inhibit melanogenesis by inhibiting the formation of reactive oxygen species⁹. Anti-tyrosinase activity of Petroselinum crispum may also contribute to its depigmenting effect. Khosravan et al reported improved melasma and decreased melasma severity in both groups applying Petroselinum crispum brewed and hydroquinone 4% cream for 8 weeks. A statistically significant difference in the mean severity of melasma was observed between both groups (n=25 for each group) from the paired t-test but not for the independent t-test, suggesting that Petroselinum crispum could be as effective as hydroquinone in improving hyperpigmentation²¹. Besides, adverse effects manifested as redness and itching were higher in subjects receiving hydroquinone. More studies are required to support the application of Petroselinum crispum as a cheaper and safer option but with similar effectiveness as hydroquinone in improving hyperpigmentation²¹.

4. Orchid and Brassocattleya marcella koss:

Plant extracts have been used in various formulations of cosmeceutical creams, particularly in combination⁷. Tadokoro et al (N=48) examined the efficacy of test formulation containing various plant extracts, including 5% orchid extract, 3% Brassocattleya marcella koss leaf/stem extract and other plant extracts which serve as moisturizing and anti-inflammatory agents on melasma and lentigo senilis. The orchid extract has been applied in cosmeceuticals for its skin moisturizing and antioxidant effects²². Both groups receiving the test formulation containing plant extracts and control formulation containing 3% vitamin-C derivative for 8 weeks have shown marked improvements in the size and colour of the pigmented spots as well as subjective surveys. Although melanin indices remained almost unchanged for both groups, global assessment of the status of pigment dispersion and spots improved significantly for the test group but not the control group²². There were no reported side effects such as irritation, itching and contact dermatitis throughout the study. Plant extracts containing orchid extract could be as effective as vitamin C derivatives as skin whitening agents in the treatment of melasma and lentigo senilis²².

B. Bioactive constituents:

1. Arbutin:

Arbutin is a hydroquinone glycoside found in the leaves of the bearberry plant, fresh fruit of California buckeye, Aesculus californica and leaves of cranberry and blueberry²³. Studies have shown that arbutin is less effective than kojic acid in the treatment of hyperpigmentation. Although higher efficacy may be achieved by increasing the concentrations, risk for paradoxical hyperpigmentation also increases⁷. Arbutin possesses tyrosinase inhibitory activity in which the inhibitory mechanism of alpha-arbutin and beta-arbutin was hypothesized to be mixed-type and non-competitive inhibition respectively²⁴.

a) Alpha-arbutin:

In a prospective study (N=35) of refractory melasma conducted by Polnikorn²⁵, topical 7% alpha-arbutin solution was applied twice a day with sunscreen after the MedLite C6 laser therapy and the results were evaluated by clinical photographs and severity grading. Overall, clinical improvements of melasma were achieved with 66.67% of the subjects had an overall good to excellent response in the reduction of melasma. The side effects reported such as discomfort, erythema and physical urticaria were resulting from the laser therapy but not arbutin²⁵. Despite, since arbutin was examined in combination with the laser treatment and there was also no comparative control group, the hypopigmentation effects of the combination therapy could not be attributed to arbutin solely and hence its effectiveness in depigmentation requires further studies. The author suggested the role of alpha-arbutin and broad-spectrum sunscreen as long-term maintenance therapy following laser treatment to prevent the recurrence of melasma²⁵. The source of arbutin was not reported by the study.

b) Beta-arbutin:

Beta-arbutin can be used to improve skin discolouration in hyperpigmentation disorders such as melasma, lentigines and ephelides. Creams containing 2.51% of arbutin obtained from the aqueous extract from the Serratula quinquefolia leaf (Serratula quinquefolia was obtained from the Garden of the Department of Medicinal and Cosmetic Natural Products, Poznan University of Medical Sciences) and without active ingredient were applied twice daily for 8 weeks by subjects with melasma and lentigo solaris²⁶. Morag et al (N=102) reported decreased melanin levels in the pigmentation spots in patients with melasma who applied the test cream. Improved skin discolourations in terms of brightened pigmentation and balancing of skin colour were also observed in female patients with melasma and lentigo solaris but the result was more prominent for melasma. Moreover, there was no reported skin irritation associated with the application of the cream throughout the study. The effectiveness of beta-arbutin in brightening and evening of skin discolourations, particularly in melasma suggested its potential as a depigmenting agent in the treatment of hyperpigmentation disorders²⁶.

2. Alpha-bisabolol:

Alpha-bisabolol is a sesquiterpene alcohol found naturally in plants such as Matricaria chamomilla, Eremanthus erythropappus, Smyrniopsis aucheri, Salvia runcinata and Vanillosmopsis species²⁷. It is known to possess several properties including anti-inflammatory, analgesic, antibiotic as well as gastric protective properties²⁸. The depigmenting effect of alpha-bisabolol is attributed to its ability to inhibit α-MSH-induced melanogenesis by blocking the phosphorylation of cAMP response element-binding (CREB) protein²⁹. Lee et al (N=28) reported significant skin lightening effects through objective assessment using spectrophotometer after the use of 0.5% alpha-bisabolol-containing cream once daily for two months compared to the vehicle control. The 98% alpha-bisabolol was purchased from Sigma Chemical Co. and was incorporated into oil-in-water cream in the concentration of 5%. However, the improvement in hyperpigmentation was not observed with respect to the clinical evaluations. There were also no reported side effects resulting from the use of the cream containing alpha-bisabolol, suggesting its potential as an adjunctive agent in the treatment of hyperpigmentation disorders²⁸.

3. Glycolic acid, salicylic acid and vitamin E:

A depigmentation cream containing several phytochemicals including 10% glycolic acid (GA), 1% Rumex occidentalis, 0.30% salicylic acid (SA), 0.25% vitamin E and other ingredients was evaluated for its safety and efficacy in the treatment of melasma by Sabancilar et al (N=27). The cream was marketed as Babe Depigmentation Cream^® with the constituents aforementioned plus other constituents such as 12% sunscreen filters, 3% milk proteins and 1% squalene. Since high concentrations of GA and SA are needed for clinical improvement of melasma, the low concentrations of GA and SA in the formulation were combined with several compounds for the synergistic hypopigmentation effects³⁰. Vitamin E acts as an antioxidant which helps to decrease the UV-induced skin damage whereas Rumex occidentalis possesses tyrosinase inhibitory activity. Application of the depigmentation cream twice a day for the first 3 months and twice a week for the subsequent 3 months yielded the results of improved melasma measured by colourimetry³⁰. The improvement was more prominent with twice daily application, suggesting the more frequent application of the depigmentation cream to achieve a better depigmenting effect. Complete removal of hyperpigmentation was not acquired, possibly due to the low concentrations of the active ingredients³⁰. Improved formulation may be needed by altering the constituents or concentrations of the active ingredients for better efficacy and safety in the treatment of melasma.

4. Bakuchiol:

Bakuchiol, a functional analogue of retinoids, is a meroterpene phenol obtained from Psoralea corylifolia, Psoralea glandulosa, Pimelea drupaceae, Ulmus davidiana, Otholobium pubescens and Piper longum with antiproliferative, anti-inﬂammatory, antioxidant and antiacne properties. The mechanism of action of bakuchiol is similar to that of retinoids³¹. Multiple mechanisms are involved in the reduction of hyperpigmentation by retinoids, including stimulation of keratinocyte turnover, decreased melanosome transfer, inhibition of tyrosinase transcription as well as inhibition of TYRP1 and TYRP2³². Bakuchiol and retinols were proposed to induce similar gene expressions which result in the cellular uptake of retinol, retinol activation in the skin as well as synthesis of extracellular matrix proteins responsible for support and integrity of the skin³³. Marked improvement was observed in the wrinkle surface area and hyperpigmentation for both groups (N=44) receiving bakuchiol (isolated from edible seeds of Psoralea corylifolia) and retinol interventions (0.5% cream for both) for 12 weeks with no statistically significant differences between both groups. However, the application of retinol 0.5% cream has been associated with more adverse effects including scaling, burning and itching compared to redness in subjects applying bakuchiol 0.5% cream. Hence, bakuchiol could be a better option to retinol due to its similar efficacy in improving photoageing and hyperpigmentation but better tolerated profiles³¹.

Table 1: Summary of the clinical studies

Plant / Plant extract / Bioactive constituent	Pigmentation disorder	Depigmenting mechanism	Comparison
Aloe vera	Melasma	Inhibit tyrosinase, decrease DOPA oxidase	Aloe vera leaf gel extract (AGE)
China camellia, Portulaca oleracea, sanchi and Prinsepia utilis herbal mixture	Melasma	Camellia inhibits tyrosinase; Portulaca oleracea has anti-inflammatory and anti-allergy activities; sanchi promotes blood circulation; Prinsepia utilis repairs skin barrier	1) Cream without active ingredient 2) Arbutin cream
Petroselinum crispum	Melasma	Inhibit tyrosinase, act as antioxidant	1) Hydroquinone 4% cream
Orchid and Brassocattleya marcella koss	Melasma and lentigo senilis	Orchid extract possesses antioxidant activities	1) Formulation containing 3% vitamin-C derivative
Alpha-arbutin	Refractory melasma	Inhibit tyrosinase and DHICA polymerase	None
Beta-arbutin	Melasma and lentigo solaris	Inhibit tyrosinase	Cream without arbutin
Alpha-bisabolol	UVA and UVB induced pigmentation (using solar simulator)	Suppress CREB phosphorylation and inhibit α-MSH induced melanogenesis	Vehicle control cream
Glycolic acid, Rumex occidentalis, salicylic acid and vitamin E	Melasma	Rumex occidentalis inhibits tyrosinase; vitamin E is an antioxidant that decreases UV-induced skin damage;	None
Bakuchiol	Hyperpigmentation	Act as an antioxidant, inhibit α-MSH activation and tyrosinase	Retinol 0.5% cream

Continue Table 1

Major results	Study limitations	Reference
1) Significant improvement (32%) in the MASI score in the liposomal-AGE treatment group compared with the control group (10%)	1) No placebo control group 2) Subjective assessment	¹⁹
1) Significant reduction in MASI scores and average melanin index for both herbal mixture cream and arbutin cream 2) Significant reduction in erythema index for herbal mixture cream	1) Herbs not studied independently 2) Criteria for clinical evaluation was not described	²⁰
1) Improved melasma and decreased melasma severity in both groups receiving parsley and hydroquinone 2) No statistically significant difference between both groups from independent t-test	1) No placebo control group 2) Subjective assessment 3) Parsley was applied brewed while hydroquinone was available as a cream	²¹
1) Significant improvements in the pigmented spots size and spot colour in both groups 2) Average melanin indices in the subjects were almost unchanged	1) Melasma type not specified 2) Phytochemicals were not studied independently 3) Formulation included licorice root extract, which has known to influence pigmentation	²²
1) 66.67% of the subjects had an overall good to excellent response in the reduction of melasma	1) No comparative control group 2) Alpha arbutin was studied in combination with laser treatment 3) Criteria for 5-point scale evaluation was not described	²⁵
1) 66.67% of the subjects had shown an improvement in skin discolourations 2) Improvement in skin discolouration is more noticeable for melasma than lentigo solaris	1) Melasma type not specified	²⁶
1) Significant skin lightening effect which improved over time than the vehicle control measured by spectrophotometer 2) No significant difference between the test and control groups for clinical improvements of the skin colour	1) The amount of cream applied depends on the area of the tested region 2) Criteria for clinical evaluation was not described	²⁸
1) Improved melasma with the use of the depigmentation cream 2) Significant improvement after twice daily application while milder effect after twice weekly application	1) No comparative control group 2) Phytochemicals were not studied independently	³⁰
1) Significant reduction in wrinkle surface area and hyperpigmentation for both bakuchiol and retinol 2) Bakuchiol was better tolerated than retinol	1) No placebo control group 2) The amount of cream applied was not fixed 3) Bakuchiol cream was applied twice while retinol cream was applied nightly	³¹

Abbreviations:

CREB, cAMP response element-binding protein; DHICA, 5,6-dihydroxyindole-2-carboxylic acid; MASI, Melasma Area and Severity Index; MSH, melanocyte-stimulating hormone

CONCLUSION:

Botanically-derived agents have been gaining increasing demand as natural alternatives to the standard treatments available in the management of hyperpigmentation disorders. These agents have been proven to be effective in depigmentation with desirable milder side effects.

Despite, the paucity of clinical studies limits the clinical application of plant-derived agents as depigmenting agents. Much of the studies conducted are mainly in vitro studies which are limited by the duration of the trials, hence questions concerning the long-term efficacy and safety of these agents remain unresolved. Among the studies included in this review, the assessment of the hypopigmentation effect varied in which some studies had both subjective and objective assessments while some only involved subjective assessment. Moreover, the objective evaluation using the device was not standardized and different equipment were used for the assessment. The clinical trials were also limited by the sample size (N=27 to N=180) and duration of the study (8 weeks to 6 months), in addition to the limitation of participant retention as loss of follow up and quitting the study due to side effects were common throughout the course of the trials. The lack of clinical trials may also be attributed to the high costs of conducting a clinical study, which makes many cosmetic pharmaceutical companies reluctant to invest in studies involving plant-derived agents. Despite, more well designed, randomized and controlled clinical studies with standardized subjective and/or objective evaluation method(s) to examine the long-term effects are needed to warrant the use of these agents.

FUNDING SUPPORT:

Pioneer Scientist Innovative Fund (PSIF) Funder: UCSI, Project Code: Proj-2019-In-FPS-019.

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Received on 22.11.2020 Modified on 29.01.2021

Research J. Pharm. and Tech 2021; 14(11):6106-6112.

DOI: 10.52711/0974-360X.2021.01061