A review on tyrosinase inhibition potential of plant extracts for skin whitening

: Fair skin is considered a trait of beauty in many cultures all over the world. Hence, there is an increased demand for skin whitening products. Since synthetic skin whitening products which are available in the market are associated with adverse effects, attention has shifted towards plant extracts with tyrosinase inhibitory potencies, as natural products are safe and effective. This study was conducted as a systematic review of plants with skin-whitening properties using a tyrosinase inhibitory assay. Research articles that were published between the years 2010-2021 were studied for this review article. The review was based on two inclusion criteria and two exclusion criteria. When it comes to inclusion criteria, tyrosinase inhibitory assay was used for extract assessment, and only the English articles were revised. The research papers that lack half maximal inhibitory concentration analysis were rejected, and only plant extracts were considered, while compounds were rejected. From a total of 70 articles that were studied, only 23 were considered relevant. IC 50 values of tyrosinase inhibitory assay in different plant extracts were considered, and the details were tabulated. The highest tyrosinase inhibitory potency was recorded from the methanol extract of Quercus infectoria galls with an IC 50 value of 3.34 µg/ml, while the second highest tyrosinase inhibitory potency was recorded from the methanol extract of Terminalia chebula fruit with an IC 50 value of 3.87 µg/ml. The families Balanophoraceae and Caprifoliaceae showed high tyrosinase inhibitory potencies, while the families Sapotaceae, Clusiaceae, Fabaceae, Solanaceae, and Malvaceae showed moderate tyrosinase inhibitory potencies. Therefore, it can be concluded that the plants from the above-mentioned families possess active tyrosinase inhibition properties. It was also observed that even when comparing the same plant part of the same species when the polarity of the solvent used for extract preparation is low that the IC 50 value tends to be high.


Introduction
Skin whitening or skin lightening is the process of using synthetic or natural substances which can even lighten the skin tone.(Burger et al., 2016).The use of various substances to whiten the skin dates back to 3000 years ago when archaeologists found records of skin protection ointments in the pyramids of ancient Egypt.(Baditha et al., 2009).Even after all these years in many countries, white skin is considered a prized asset.Over the past years, an increasing trend in skin whitening has been observed in South Asian countries such as Sri Lanka, India, Pakistan, and Bangladesh.(Baditha et al., 2009).
Over the past years, the production and marketing of skin whitening products has become a multi-billion-dollar industry.(Aramide et al., 2019).Skin whitening is done for many reasons, including white supremacy, slavery, Eurocentric beauty standards, colonization, external racism by white people, internal racism by black people, and stereotyping of femininity and masculinity.(Aramide et al., 2019).Sources suggest that the belief in darker skin is associated with lower status and lesser beauty, resulting in feelings of poor identity, inferiority, and low self-esteem, which leads people towards skin whitening.(Lewis et al., 2011).
The primary determinant of skin color is called Melanin, which protects the skin by absorbing UV radiation.(Liyanaarachchi et al., 2018).Melanin is produced through a process called melanogenesis, and Melanin is synthesized in the basal layer of the epidermis in the melanocytes.(Napagoda et al., 2018).Melanogenesis is initiated by an enzyme called tyrosinase.(Perera et al., 2017).Studies have proven that substances that possess the ability to inhibit the catalytic activity of tyrosinase can interrupt the synthesis and release of Melanin.Therefore, tyrosinase inhibition is a commonly used strategy in skin whitening.(Burger et al., 2016).
Synthetic skin whitening products available in the market contain various harmful compounds which can have adverse effects such as acne breakouts, uneven skin, and dullness.Long-term use of these products can lead to tumors, kidney diseases, and many undesirable effects.(Wijesekara and De Silva, 2019).Increased demand for whitening skin products has been observed across Asia, making identifying new compounds with skin-whitening properties necessary.(Perera et al., 2018).Skin whitening properties have been observed in both natural and artificial sources.Many natural sources such as plants, fungi, bacteria, and algae have proven to consist skinwhitening properties.Both medicinal and non-medicinal plants have proven to consist skin-whitening properties with low toxicity and high efficiency.(Hashemi and Zarei, 2014).
The plant extracts that showed IC 50 values less than 20 µg/ml in tyrosinase inhibitory assay were considered as plant extracts with high tyrosinase inhibitory potencies.The methanol extract of Quercus infectoria (Fagaceae) galls on leaves showed the highest tyrosinase inhibitory potency with an IC 50 value of 3.34 µg/ml.(Ansari et al., 2011).This plant is best suited to produce a skin whitening product such as a cream, a lotion, or a soap.Also, other plant species from the family Fagaceae might contain high tyrosinase inhibitory potencies, thus, effective skin whitening properties.The methanol extract of Terminalia chebula (Combretaceae) showed an IC 50 value of 3.87 µg/ml.(Ansari et al., 2011).Since the plant Terminalia chebula showed the second highest tyrosinase inhibitory potency, this plant might also be highly effective when it comes to skin whitening product development.Furthermore, other plant species from the family Combretaceae might contain high tyrosinase inhibitory potencies.The ethyl acetate of the Balanophora laxiflora (Balanophoraceae) plant showed an IC 50 value of 7.90 µg/ml.In contrast, the butanol extract of the plant showed an IC 50 value of 15.12 µg/ml (Hang et al., 2016).The flowers, leaves, and branches of the species Lonicera japonica (Caprifolaceae) showed high tyrosinase inhibitory potencies.Because many plant parts from the species Lonicera japonica show high tyrosinase inhibitory potencies, this plant can be valuable for skin whitening product development.Further studies are needed to evaluate the full potential of this plant.The aqueous extract of leaves of Euginea dysenterica (Myrtaceae) showed a high tyrosinase inhibitory potency with an IC 50 value of 11.88 µg/ml.(Sauza et al., 2012).The aqueous extract of Quercus infectoria showed an IC 50 value of 14.7 µg/ml.(Ansari et al., 2011).
Even though the methanol extract of Quercus infectoria galls showed the highest tyrosinase inhibitory potency when considering the obtained results, it was observed that the aqueous extract of the Quercus infectoria galls gave a lesser tyrosinase inhibitory activity in comparison.Therefore, methanol extracts are more potent than aqueous extracts and, thus, more suitable for further research on the skin-whitening properties of plants and natural skin-whitening product development.
When considering the overall results, it was observed that the methanol extract of plants is more suitable for tyrosinase inhibitory assay since methanol extracts of plant parts show high tyrosinase inhibitory potencies.This can be due to the difference in polarities in organic solvents which are used for extract preparation.When considering the plant species mentioned above, many of these plants belong to the plant families Balanophoraceae and Caprifoliaceae.Therefore, these two plant families might contain high tyrosinase inhibitory potencies.Furthermore, other plant species which belong to the families mentioned above might possess high tyrosinase inhibitory potencies.When considering the evaluated plant parts, leaves and flowers had shown high tyrosinase inhibitory potencies.Therefore, leaves and flowers from plants that belong to the families Balanophoraceae and Caprifoliaceae might possess high tyrosinase inhibitory potencies, thus effective skin whitening properties.Moreover, once known for certain, if they contain skin-whitening properties, leaves and flowers from plants that belong to the above-mentioned families can be used for novel skin-whitening product development.
The plant extracts that showed IC 50 values within the range of (20 µg/ml < IC 50< 200 µg/ml) in tyrosinase inhibitory assay were considered as plant extracts with moderate tyrosinase inhibitory potencies.When considering the moderate tyrosinase inhibitory potencies, Pouteria torta and Pouteria caimito, which belong to the family Sapotaceae, showed moderate tyrosinase inhibitory potencies.The aqueous extract of leaves of Pouteria torta showed an IC 50 value of 30.01 µg/ml, while the aqueous extract of leaves of Pouteria caimito showed an IC 50 value of 50.01µg/ml.(Souza et al., 2012).The species Garcinia atroviridis, Calophyllum symingtonianum, and Calophyllum depressinervosum, which belong to the family Clusiaceae, showed moderate tyrosinase inhibitory potencies.The plant family Fabaceae showed moderate tyrosinase inhibitory potencies, whereas the species Cassia auriculata, Stryphodendron adstringens, Saraca asoca showed moderate tyrosinase inhibitory potencies.(Stankovic et al., 2019) extract of leaves of Saraca asoca showed an IC 50 value of 53.5 µg/ml.(Perera et al., 2017).
When it comes to the family Solanaceae, the species Lycoperssicon esculentum and Physalis alkekengi showed moderate tyrosinase inhibitory potencies.Under the species Lycopersicon esculentum, the verities Eva F1 and Hausa were considered.When comparing the two verities, Eva F1 verity showed a high tyrosinase inhibitory potency with the IC 50 value of 65 µg/ml for methanol extract of the leaves.(Omatoyinbo et al., 2020).In the family Malvaceae, the species Thespesia populnea and Hibiscus tiliaceus showed moderate tyrosinase inhibitory potencies, where methanol extract of Thespesia populnea bark showed the IC 50 value of 190 µg/ml (Perera et al., 2018) while the dichloromethane extract of leaves of Hibiscus tiliaceus showed the IC 50 value of 130 µg/ml.(Lim et al., 2021).Since the leaves and fruit peel of Pouteria torta, as well as leaves, seeds, and bark of Saraca asoca, showed moderate tyrosinase inhibitory potencies, these two plant species contain considerable skin whitening properties; thus, these two species can be used for product development in skin whitening products.When considering the families these plants be-long to, it was observed that many plants with moderate tyrosinase inhibitory potency belong to the families of Sapotaceae, Clusiaceae, Fabaceae, Solanaceae, and Malvaceae.Therefore, the above-mentioned families contain considerable skin-whitening properties.
Furthermore, other plant species belonging to the abovementioned plant families might also contain many skinwhitening properties.When considering the plant parts, leaves contain a considerable amount of tyrosinase inhibitory potency in many plant species.Therefore, the leaves show higher tyrosinase inhibitory potency and skin-whitening properties compared to other plant parts.The plant species' aerial parts, bark stem, bark, and fruit peel also showed many skin-whitening properties.Given that, leaves from plants that belong to families Sapotaceae, Clusiaceae, Fabaceae, Solanaceae, and Malvaceae might contain moderate or even high tyrosinase inhibitory properties, thus skin whitening properties.Leaves from the plants belonging to the above-mentioned families can be used to produce skinwhitening products.
The plant extracts that showed IC 50 values within the range of (200 µg/ml < IC 50< 1000 µg/ml) in tyrosinase inhibitory assay were considered as plant extracts with low tyrosinase inhibitory potencies.Blumea balsamifera and Tagetes erecta, which belong to the family Asteraceae showed low tyrosinase inhibitory potencies.When considering the family Sapotaceae, the species Pouteria ramiflora and Pouteria torta were evaluated for their tyrosinase inhibitory potencies.When comparing the two verities, the species Pouteria ramiflora showed a high tyrosinase inhibitory potency compared with the ethanol extract of leaves showing the IC 50 value of 249.83 µg/ml.In contrast, the ethanol extract of the Pouteria torta leaves showed an IC 50 value of 258.53 µg/ml.(Souza et al., 2012).The petroleum ether extract of Citrus sinensis Osbeck cv Newhall (Rutaceae) peel showed an IC 50 value of 250.31 µg/ml.
The ethanol extract of the peel and the aqueous extract of the peel showed significantly lower IC 50 values than the petroleum ether extract.(Guo et al., 2020).This can be due to the polarities of the solvent, where petroleum ether has significantly less polarity (non-polar) when compared to the other two solvents.Ethanol has a polarity less than water but higher than petroleum ether.Therefore, the ethanol extract of the Citrus sinensis peel showed an IC 50 value higher than the aqueous extract but lesser than the petroleum ether extract.This theory about less polarity of the organic solvent correlating with a higher IC 50 value can be proven further, where the acetone extract of Sonneratia alba (Lythraceae) leaves showed the IC 50 value of 550 µg/ml.
In comparison, the methanol extract of Sonneratia alba leaves showed an IC 50 value of 650 µg/ml.(Lim et al., 2021).Acetone has a lesser polarity than methanol; thus, it gave a high IC 50 value even for the same plant part of the same species.In the family Rhizophoraceae, Rhizophora apiculata, and Rhizophora mucronata species were evaluated for their tyrosinase inhibitory potencies.When comparing the two species, Rhizophora apiculata showed considerably high tyrosinase inhibitory potencies in comparison to Rhizophora mucronata where the methanol extract of Rhizophora apiculata leaves showed the IC 50 value of 280 µg/ml.In contrast, the methanol extract of Rhizophora mucronata showed an IC 50 value of 790 µg/ml (Lim et al., 2021).
The more studies which might lead to the development of natural skin whitening products with fewer adverse effects and better safety.

Conclusion
When considering the analyzed data, it was observed that the majority of the plants reviewed contained moderate or low tyrosinase inhibitory potencies.The highest tyrosinase inhibitory potency was recorded from the methanol extract of Quercus infectoria galls on leaves with the IC 50 value of 3.34 µg/ml.In comparison, the second-highest tyrosinase inhibitory potency was recorded from the methanol extract of Terminalia chebula fruit with an IC 50 value of 3.87 µg/ml.The species Quercus infectoria is the best plant species that can be used to develop skin whitening products.The species Quercus infectoria belongs to the family Fagaceae.Hence, the family Fagaceae needs more attention and research, which will help develop novel skinwhitening products.
Furthermore, the families Balanophoraceae and Caprifoliaceae showed high tyrosinase inhibitory potencies.The families Sapotaceae, Clusiaceae, Fabaceae, Solanaceae, and Malvaceae showed moderate tyrosinase inhibitory potencies.Therefore, further research is required on other plants belonging to the families mentioned above as they might also contain considerable tyrosinase inhibitory potencies.In all plants, the leaves showed higher, if not considerable, tyrosinase inhibitory potencies, thus skin whitening properties.It was also observed that even when comparing the same plant part of the same species when the polarity of the solvent used for extract preparation is low, the IC 50 value tends to be high.Since many plant parts of the species Lonicera Japonia, Pouteria torta, and Saraca asoca, including flowers, leaves, and branches of Lonicera Japonia, leaves and fruit peel of Pouteria torta and leaves, seed, the bark of Saraca asoca showed tyrosinase inhibitory potencies these species need to be more attentive.

Table 3 :
Moderate tyrosinase inhibitory potencies of plant species (200 µg/ml<IC 50 < 1000 µg/ml) majority of plants that showed low tyrosinase inhibitory potencies belong to the family Polygonaceae, where four species, namely, Polygonum sachalinense, Persicaria sieboldi, Polygonum alpinum and Polygonum cuspidata were evaluated for tyrosinase inhibitory potencies.When comparing the tyrosinase inhibitory potencies of those above-mentioned four plants the species Polygonum sachalinense showed significantly high tyrosinase inhibitory potencies in comparison to other species from the family Polygonaceae.In the family Malvaceae, the species Alcea rosea and Hibiscus tiliaceus were evaluated for tyrosinase inhibitory potencies.When considering the family Rosaceae, the species Fragaria ananassa and Prunus spinosa L were evaluated for tyrosinase inhibitory potencies, where the species showed low tyrosinase inhibitory potencies.The methanol extract of the fruit of the Prunus spinosa L showed an IC 50 value of 636.51 µg/ml.