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Kojic acid has many uses in dermatologic products, primarily as a skin lightener, but concerns about its irritant properties have limited its role in cosmetics. Research on kojic acid shows both its promise and some evidence to support restrictions on its widespread use.
Kojic acid (5-hydroxy-2[hydroxymethyl]-gamma-pyrone, or C6H6O4), a hydrophilic fungal metabolite derived from various species of Aspergillus, Acetobacter, and Penicillium, is commonly used as a treatment for hyperpigmentation disorders (Biochem. Mol. Biol. Int. 1994;32:731-5; Contact Dermatitis 1998;39:86-7), as a food additive for preventing enzymatic browning, and as an agent to promote the reddening of unripe strawberries (J. Sci. Food. Agr. 1977;28:243). It was discovered as a fungal natural product in 1907 (Nat. Prod. Rep. 2006;23:1046-62). Kojic acid exerts a slow-binding inhibition of tyrosinase activity, mainly by chelating copper (Dermatol. Clin. 2007;25:337-42; J. Pharm. Pharmacol. 1994;46:982-5; Phytother. Res. 2006;20:921-34), and the result is a cutaneous whitening effect.
The efficacy of kojic acid in achieving such an effect is similar to that of hydroquinone, the standard and yet still controversial depigmenting agent (Dermatol. Ther. 2004;17:151-7; Skin Therapy Lett. 2004;9:1-3). Used mainly as a skin-lightening agent, kojic acid also exhibits antibiotic, anti-inflammatory, and anodyne properties (Dermatol. Clin. 2007;25:337-42). In addition, it is used in Asia as a dietary antioxidant (Phytother. Res. 2006;20:921-34; Dermatol. Surg. 1999;25:282-4).
Treatment of Hyperpigmentation
Manufacturers, especially in Japan, have used kojic acid since 1988 in cosmetic agents for its capacity to decrease pigmentation (Semin. Cutan. Med. Surg. 2009;28:77-85; J. Pharm. Pharmacol. 1994;46:982-5). In cosmetic formulations, kojic acid enhances the shelf life of products by dint of its preservative and antibiotic activity (Cent. Eur. J. Public Health. 2004;12 [Suppl]:S16-8). Its stability is one of the advantages of kojic acid over hydroquinone and other skin-lightening ingredients (Regul. Toxicol. Pharmacol. 2001;33:80-101).
In two studies, kojic acid combined with glycolic acid was demonstrated to be more effective than 10% glycolic acid combined with 4% hydroquinone for the treatment of hyperpigmentation (Facial Plast. Surg. 1995;11:15-21; Dermatol. Surg. 1996;22:443-7). In one case, Garcia and Fulton set out to assess and compare the effects on melasma and other pigmentary conditions of a glycolic acid/hydroquinone formulation and a glycolic acid/kojic acid formulation. Wood’s light and UV light photography were used to evaluate the effects of the different compounds, one on each side of the face, in 39 patients. The investigators found no statistically significant differences between the reactions; in all, 28% of the patients experienced marked improvements on the kojic acid side, 21% on the hydroquinone side. The responses to each formulation were equal in 51% of the participants. Although the kojic acid formulation was considered more irritating, the investigators found both formulations effective in treating melasma (Dermatol. Surg. 1996;22:443-7).
Treatment for Melasma
Lim studied the effects on melasma of 2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone in 40 Chinese women with epidermal melasma. In this 12-week study, subjects were treated with the test formulation, in randomized fashion, on one side of the face and the same formulation minus kojic acid on the other side. Self-assessment questionnaires every 4 weeks, photographs, and clinical evaluations were used to rate the efficacy of the treatment. Lim found that the addition of kojic acid to the glycolic acid/hydroquinone gel improved melasma. Specifically, more than half of the melasma cleared in 24 of 40 patients who received the kojic acid formulation, compared with 19 of 40 who received the kojic acid–free gel. Two patients experienced complete clearance, in both cases on the side of the face on which the kojic acid gel was used (Dermatol. Surg. 1999;25:282-4). Two years later, Ferioli and colleagues found that combining hydroquinone and kojic acid exerted a synergistic effect, with an equimolecular distribution achieving the optimal result (Int. J. Cosmet. Sci. 2001;23:333-40).
As a lone therapy for the treatment of melasma, however, kojic acid is a member of the arsenal but is one of the last options typically selected (Dermatol. Clin. 2007;25:337-42), because it may be irritating to the skin (Skin Therapy Lett. 2006;11:1-6; Dermatol. Nurs. 2004;16:401-6, 413-6). It can be effective, though, in patients who do not tolerate the first-line products, particularly hydroquinone (Dermatol. Nurs. 2004;16:401-6, 413-6). Furthermore, combining a topical corticosteroid with kojic acid can reduce the irritant qualities of the fungal derivative (Int. J. Dermatol. 1998;37:897-903; Phytother. Res. 2006;20:921-34). In the experimental setting, kojic acid is regularly used as a reference or positive control to test the skin-whitening potential of new agents.
Antiwrinkle Properties
Other applications of kojic acid have also been considered. In 2001, Mitani and colleagues investigated the potential antiwrinkle activity of kojic acid given the iron-chelating properties of the acid and the known association between chronic photodamage and cutaneous iron. Over 20 weeks, the investigators topically applied kojic acid prior to exposing hairless mice to UV radiation. The agent successfully inhibited wrinkle development, epidermal hyperplasia, lower dermis fibrosis, and increases in upper dermis extracellular matrix components (Eur. J. Pharmacol. 2001;411:169-74).
Skin-Lightening Properties
The primary use for kojic acid in dermatology, though, remains skin whitening. Kojic acid is second only to hydroquinone in terms of effectiveness as a skin-lightening agent in topical, over-the-counter products (Dermatol. Ther. 2007;20:308-13), and is the most popular agent for treating melasma in East Asia (Dermatol. Surg. 1999;25:282-4; Dermatol. Ther. 2007;20:308-13).This makes sense, given the increasing regulatory scrutiny of hydroquinone, which has been banned in Europe and is tightly regulated in Asia, while remaining available, however tenuously, in the United States. Kojic acid is also a sensitizer. Mild facial erythema is the primary adverse effect reported in association with the typically well-tolerated fungal metabolite (Dermatol. Clin. 2007;25:353-62), which has been banned and then permitted to return to the market as a skin-lightening agent (Dermatol. Ther. 2007;20:308-13).
Kojic acid products are typically used twice daily for 1 to 2 months or until the patient achieves the desired results. Unfortunately, kojic acid has reportedly provoked contact allergies and is considered to exhibit a high sensitizing potential (Contact Dermatitis 1995;32:9-13). Because preparations containing a 2.5% concentration of kojic acid have been associated with facial dermatitis, a concentration of 1% has become more common. However, there have also been some reports of sensitization linked to 1% creams (Contact Dermatitis 1995;32:9-13). As kojic acid has also been extensively used in foods, there have been many reports on its oral safety. In addition, injecting kojic acid has the potential to induce convulsions (Regul. Toxicol. Pharmacol. 2001;33:80-101).
Possible Link With Tumor Promotion
Despite the success of kojic acid at 1% concentrations, particularly in Japan, some studies have indicated that longer term use of the agent may engender contact dermatitis and erythema (Skin Therapy Lett. 2004;9:1-3; Contact Dermatitis 1998;39:86-7; Contact Dermatitis 1995;32:9-13). In addition, an association between hepatic tumors in heterozygous p53-deficient mice and the topical application of kojic acid has been identified (Toxicol. Sci. 2003;73:287-93; Dermatol. Clin. 2007;25:353-62). In 2003, Japan’s health ministry ordered the removal of kojic acid from the market over fears, based on animal studies, that the fungal metabolite might cause cancer (Nature 2004;432:938).
In response to such findings and concerns, specifically the link between potential tumor promotion in mouse and rat livers caused by use of kojic acid, Higa and colleagues examined the presence of initiation activity in rat liver and the potential of photogenotoxicity and carcinogenicity in mouse skin in relation to kojic acid. In one of the team’s multiple experiments, a cream containing 1.0% or 3.0% kojic acid was applied twice to the backs of mice in a 24-hour period, and researchers noted that kojic acid failed to induce epidermal cell micronuclei. In addition, a skin carcinogenesis bioassay for initiation-promotion potential revealed the emergence of no skin nodules that were caused by the topical application of 3.0% kojic acid cream to the backs of mice daily for 7 days or five times a week for 19 weeks, administered during either cancer stage. Overall, the investigators concluded that kojic acid posed a minimal risk of photocarcinogenesis in the skin and did not exhibit skin carcinogenesis initiation nor promotion activity. The findings also lent support to the contention that kojic acid is a safe ingredient in cosmeceuticals (J. Toxicol. Sci. 2007;32:143-59). In addition, Lee and colleagues recently reported on derivatives of kojic acid displaying greater efficiency through increased penetration into the skin (Arch. Pharm. (Weinheim) 2006;339:111-4).
Previously, in 2003, Kim and colleagues studied the effects of a stable kojic acid derivative, 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one (Kojyl-APPA), on tyrosinase activity and melanin production. The investigators found that Kojyl-APPA is not a direct inhibitor of tyrosinase, but is enzymatically converted to kojic acid in cells. However, the derivative was found to suppress tyrosinase activity markedly 24 hours after treatment in normal human melanocytes and demonstrated a 30% inhibition of tyrosinase in situ (although not in vitro). The kojic acid derivative also lowered melanin content to 75% of control in melanoma cells and neomelanin production to 43% of control in normal human melanocytes. Notably, Kojyl-APPA had an eightfold greater capacity to permeate the skin than did kojic acid (Chem. Pharm. Bull. (Tokyo) 2003;51:113-6). A kojic acid derivative found to be eight times more potent than kojic acid as a tyrosinase inhibitor was also synthesized in 2006. The compound produced by Lee and colleagues also displayed strong inhibitory activity toward melanin production (Arch. Pharm. (Weinheim) 2006;33:111-4).
It is worth noting that although kojic acid yields greater stability than does hydroquinone, the fungal derivative does have labile oxidative properties, which are enhanced by light and heat exposure. For that reason, the inclusion of kojic acid in cosmetic formulations has been through its dipalmitic ester (as kojic dipalmitate) (Talanta 2008;75:407-1).
Conclusion
The fungal derivative kojic acid has maintained a significant role in the dermatologic armamentarium for 2 decades as a skin-whitening agent and is best used in combination with other depigmenting ingredients, which enhance the overall effect of the formulation and blunt the irritating effects of kojic acid. Recent evidence has allayed fears regarding long-term carcinogenic effects, but as always, research is ongoing to develop newer, safer derivatives.
Dr. Baumann writes the column “Cosmeceutical Critique,” which regularly appears in Skin & Allergy News. She is in private practice in Miami Beach. To respond to this column, or to suggest topics for future columns, e-mail her at sknews@elsevier.com.
Kojic acid has many uses in dermatologic products, primarily as a skin lightener, but concerns about its irritant properties have limited its role in cosmetics. Research on kojic acid shows both its promise and some evidence to support restrictions on its widespread use.
Kojic acid (5-hydroxy-2[hydroxymethyl]-gamma-pyrone, or C6H6O4), a hydrophilic fungal metabolite derived from various species of Aspergillus, Acetobacter, and Penicillium, is commonly used as a treatment for hyperpigmentation disorders (Biochem. Mol. Biol. Int. 1994;32:731-5; Contact Dermatitis 1998;39:86-7), as a food additive for preventing enzymatic browning, and as an agent to promote the reddening of unripe strawberries (J. Sci. Food. Agr. 1977;28:243). It was discovered as a fungal natural product in 1907 (Nat. Prod. Rep. 2006;23:1046-62). Kojic acid exerts a slow-binding inhibition of tyrosinase activity, mainly by chelating copper (Dermatol. Clin. 2007;25:337-42; J. Pharm. Pharmacol. 1994;46:982-5; Phytother. Res. 2006;20:921-34), and the result is a cutaneous whitening effect.
The efficacy of kojic acid in achieving such an effect is similar to that of hydroquinone, the standard and yet still controversial depigmenting agent (Dermatol. Ther. 2004;17:151-7; Skin Therapy Lett. 2004;9:1-3). Used mainly as a skin-lightening agent, kojic acid also exhibits antibiotic, anti-inflammatory, and anodyne properties (Dermatol. Clin. 2007;25:337-42). In addition, it is used in Asia as a dietary antioxidant (Phytother. Res. 2006;20:921-34; Dermatol. Surg. 1999;25:282-4).
Treatment of Hyperpigmentation
Manufacturers, especially in Japan, have used kojic acid since 1988 in cosmetic agents for its capacity to decrease pigmentation (Semin. Cutan. Med. Surg. 2009;28:77-85; J. Pharm. Pharmacol. 1994;46:982-5). In cosmetic formulations, kojic acid enhances the shelf life of products by dint of its preservative and antibiotic activity (Cent. Eur. J. Public Health. 2004;12 [Suppl]:S16-8). Its stability is one of the advantages of kojic acid over hydroquinone and other skin-lightening ingredients (Regul. Toxicol. Pharmacol. 2001;33:80-101).
In two studies, kojic acid combined with glycolic acid was demonstrated to be more effective than 10% glycolic acid combined with 4% hydroquinone for the treatment of hyperpigmentation (Facial Plast. Surg. 1995;11:15-21; Dermatol. Surg. 1996;22:443-7). In one case, Garcia and Fulton set out to assess and compare the effects on melasma and other pigmentary conditions of a glycolic acid/hydroquinone formulation and a glycolic acid/kojic acid formulation. Wood’s light and UV light photography were used to evaluate the effects of the different compounds, one on each side of the face, in 39 patients. The investigators found no statistically significant differences between the reactions; in all, 28% of the patients experienced marked improvements on the kojic acid side, 21% on the hydroquinone side. The responses to each formulation were equal in 51% of the participants. Although the kojic acid formulation was considered more irritating, the investigators found both formulations effective in treating melasma (Dermatol. Surg. 1996;22:443-7).
Treatment for Melasma
Lim studied the effects on melasma of 2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone in 40 Chinese women with epidermal melasma. In this 12-week study, subjects were treated with the test formulation, in randomized fashion, on one side of the face and the same formulation minus kojic acid on the other side. Self-assessment questionnaires every 4 weeks, photographs, and clinical evaluations were used to rate the efficacy of the treatment. Lim found that the addition of kojic acid to the glycolic acid/hydroquinone gel improved melasma. Specifically, more than half of the melasma cleared in 24 of 40 patients who received the kojic acid formulation, compared with 19 of 40 who received the kojic acid–free gel. Two patients experienced complete clearance, in both cases on the side of the face on which the kojic acid gel was used (Dermatol. Surg. 1999;25:282-4). Two years later, Ferioli and colleagues found that combining hydroquinone and kojic acid exerted a synergistic effect, with an equimolecular distribution achieving the optimal result (Int. J. Cosmet. Sci. 2001;23:333-40).
As a lone therapy for the treatment of melasma, however, kojic acid is a member of the arsenal but is one of the last options typically selected (Dermatol. Clin. 2007;25:337-42), because it may be irritating to the skin (Skin Therapy Lett. 2006;11:1-6; Dermatol. Nurs. 2004;16:401-6, 413-6). It can be effective, though, in patients who do not tolerate the first-line products, particularly hydroquinone (Dermatol. Nurs. 2004;16:401-6, 413-6). Furthermore, combining a topical corticosteroid with kojic acid can reduce the irritant qualities of the fungal derivative (Int. J. Dermatol. 1998;37:897-903; Phytother. Res. 2006;20:921-34). In the experimental setting, kojic acid is regularly used as a reference or positive control to test the skin-whitening potential of new agents.
Antiwrinkle Properties
Other applications of kojic acid have also been considered. In 2001, Mitani and colleagues investigated the potential antiwrinkle activity of kojic acid given the iron-chelating properties of the acid and the known association between chronic photodamage and cutaneous iron. Over 20 weeks, the investigators topically applied kojic acid prior to exposing hairless mice to UV radiation. The agent successfully inhibited wrinkle development, epidermal hyperplasia, lower dermis fibrosis, and increases in upper dermis extracellular matrix components (Eur. J. Pharmacol. 2001;411:169-74).
Skin-Lightening Properties
The primary use for kojic acid in dermatology, though, remains skin whitening. Kojic acid is second only to hydroquinone in terms of effectiveness as a skin-lightening agent in topical, over-the-counter products (Dermatol. Ther. 2007;20:308-13), and is the most popular agent for treating melasma in East Asia (Dermatol. Surg. 1999;25:282-4; Dermatol. Ther. 2007;20:308-13).This makes sense, given the increasing regulatory scrutiny of hydroquinone, which has been banned in Europe and is tightly regulated in Asia, while remaining available, however tenuously, in the United States. Kojic acid is also a sensitizer. Mild facial erythema is the primary adverse effect reported in association with the typically well-tolerated fungal metabolite (Dermatol. Clin. 2007;25:353-62), which has been banned and then permitted to return to the market as a skin-lightening agent (Dermatol. Ther. 2007;20:308-13).
Kojic acid products are typically used twice daily for 1 to 2 months or until the patient achieves the desired results. Unfortunately, kojic acid has reportedly provoked contact allergies and is considered to exhibit a high sensitizing potential (Contact Dermatitis 1995;32:9-13). Because preparations containing a 2.5% concentration of kojic acid have been associated with facial dermatitis, a concentration of 1% has become more common. However, there have also been some reports of sensitization linked to 1% creams (Contact Dermatitis 1995;32:9-13). As kojic acid has also been extensively used in foods, there have been many reports on its oral safety. In addition, injecting kojic acid has the potential to induce convulsions (Regul. Toxicol. Pharmacol. 2001;33:80-101).
Possible Link With Tumor Promotion
Despite the success of kojic acid at 1% concentrations, particularly in Japan, some studies have indicated that longer term use of the agent may engender contact dermatitis and erythema (Skin Therapy Lett. 2004;9:1-3; Contact Dermatitis 1998;39:86-7; Contact Dermatitis 1995;32:9-13). In addition, an association between hepatic tumors in heterozygous p53-deficient mice and the topical application of kojic acid has been identified (Toxicol. Sci. 2003;73:287-93; Dermatol. Clin. 2007;25:353-62). In 2003, Japan’s health ministry ordered the removal of kojic acid from the market over fears, based on animal studies, that the fungal metabolite might cause cancer (Nature 2004;432:938).
In response to such findings and concerns, specifically the link between potential tumor promotion in mouse and rat livers caused by use of kojic acid, Higa and colleagues examined the presence of initiation activity in rat liver and the potential of photogenotoxicity and carcinogenicity in mouse skin in relation to kojic acid. In one of the team’s multiple experiments, a cream containing 1.0% or 3.0% kojic acid was applied twice to the backs of mice in a 24-hour period, and researchers noted that kojic acid failed to induce epidermal cell micronuclei. In addition, a skin carcinogenesis bioassay for initiation-promotion potential revealed the emergence of no skin nodules that were caused by the topical application of 3.0% kojic acid cream to the backs of mice daily for 7 days or five times a week for 19 weeks, administered during either cancer stage. Overall, the investigators concluded that kojic acid posed a minimal risk of photocarcinogenesis in the skin and did not exhibit skin carcinogenesis initiation nor promotion activity. The findings also lent support to the contention that kojic acid is a safe ingredient in cosmeceuticals (J. Toxicol. Sci. 2007;32:143-59). In addition, Lee and colleagues recently reported on derivatives of kojic acid displaying greater efficiency through increased penetration into the skin (Arch. Pharm. (Weinheim) 2006;339:111-4).
Previously, in 2003, Kim and colleagues studied the effects of a stable kojic acid derivative, 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one (Kojyl-APPA), on tyrosinase activity and melanin production. The investigators found that Kojyl-APPA is not a direct inhibitor of tyrosinase, but is enzymatically converted to kojic acid in cells. However, the derivative was found to suppress tyrosinase activity markedly 24 hours after treatment in normal human melanocytes and demonstrated a 30% inhibition of tyrosinase in situ (although not in vitro). The kojic acid derivative also lowered melanin content to 75% of control in melanoma cells and neomelanin production to 43% of control in normal human melanocytes. Notably, Kojyl-APPA had an eightfold greater capacity to permeate the skin than did kojic acid (Chem. Pharm. Bull. (Tokyo) 2003;51:113-6). A kojic acid derivative found to be eight times more potent than kojic acid as a tyrosinase inhibitor was also synthesized in 2006. The compound produced by Lee and colleagues also displayed strong inhibitory activity toward melanin production (Arch. Pharm. (Weinheim) 2006;33:111-4).
It is worth noting that although kojic acid yields greater stability than does hydroquinone, the fungal derivative does have labile oxidative properties, which are enhanced by light and heat exposure. For that reason, the inclusion of kojic acid in cosmetic formulations has been through its dipalmitic ester (as kojic dipalmitate) (Talanta 2008;75:407-1).
Conclusion
The fungal derivative kojic acid has maintained a significant role in the dermatologic armamentarium for 2 decades as a skin-whitening agent and is best used in combination with other depigmenting ingredients, which enhance the overall effect of the formulation and blunt the irritating effects of kojic acid. Recent evidence has allayed fears regarding long-term carcinogenic effects, but as always, research is ongoing to develop newer, safer derivatives.
Dr. Baumann writes the column “Cosmeceutical Critique,” which regularly appears in Skin & Allergy News. She is in private practice in Miami Beach. To respond to this column, or to suggest topics for future columns, e-mail her at sknews@elsevier.com.
Kojic acid has many uses in dermatologic products, primarily as a skin lightener, but concerns about its irritant properties have limited its role in cosmetics. Research on kojic acid shows both its promise and some evidence to support restrictions on its widespread use.
Kojic acid (5-hydroxy-2[hydroxymethyl]-gamma-pyrone, or C6H6O4), a hydrophilic fungal metabolite derived from various species of Aspergillus, Acetobacter, and Penicillium, is commonly used as a treatment for hyperpigmentation disorders (Biochem. Mol. Biol. Int. 1994;32:731-5; Contact Dermatitis 1998;39:86-7), as a food additive for preventing enzymatic browning, and as an agent to promote the reddening of unripe strawberries (J. Sci. Food. Agr. 1977;28:243). It was discovered as a fungal natural product in 1907 (Nat. Prod. Rep. 2006;23:1046-62). Kojic acid exerts a slow-binding inhibition of tyrosinase activity, mainly by chelating copper (Dermatol. Clin. 2007;25:337-42; J. Pharm. Pharmacol. 1994;46:982-5; Phytother. Res. 2006;20:921-34), and the result is a cutaneous whitening effect.
The efficacy of kojic acid in achieving such an effect is similar to that of hydroquinone, the standard and yet still controversial depigmenting agent (Dermatol. Ther. 2004;17:151-7; Skin Therapy Lett. 2004;9:1-3). Used mainly as a skin-lightening agent, kojic acid also exhibits antibiotic, anti-inflammatory, and anodyne properties (Dermatol. Clin. 2007;25:337-42). In addition, it is used in Asia as a dietary antioxidant (Phytother. Res. 2006;20:921-34; Dermatol. Surg. 1999;25:282-4).
Treatment of Hyperpigmentation
Manufacturers, especially in Japan, have used kojic acid since 1988 in cosmetic agents for its capacity to decrease pigmentation (Semin. Cutan. Med. Surg. 2009;28:77-85; J. Pharm. Pharmacol. 1994;46:982-5). In cosmetic formulations, kojic acid enhances the shelf life of products by dint of its preservative and antibiotic activity (Cent. Eur. J. Public Health. 2004;12 [Suppl]:S16-8). Its stability is one of the advantages of kojic acid over hydroquinone and other skin-lightening ingredients (Regul. Toxicol. Pharmacol. 2001;33:80-101).
In two studies, kojic acid combined with glycolic acid was demonstrated to be more effective than 10% glycolic acid combined with 4% hydroquinone for the treatment of hyperpigmentation (Facial Plast. Surg. 1995;11:15-21; Dermatol. Surg. 1996;22:443-7). In one case, Garcia and Fulton set out to assess and compare the effects on melasma and other pigmentary conditions of a glycolic acid/hydroquinone formulation and a glycolic acid/kojic acid formulation. Wood’s light and UV light photography were used to evaluate the effects of the different compounds, one on each side of the face, in 39 patients. The investigators found no statistically significant differences between the reactions; in all, 28% of the patients experienced marked improvements on the kojic acid side, 21% on the hydroquinone side. The responses to each formulation were equal in 51% of the participants. Although the kojic acid formulation was considered more irritating, the investigators found both formulations effective in treating melasma (Dermatol. Surg. 1996;22:443-7).
Treatment for Melasma
Lim studied the effects on melasma of 2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone in 40 Chinese women with epidermal melasma. In this 12-week study, subjects were treated with the test formulation, in randomized fashion, on one side of the face and the same formulation minus kojic acid on the other side. Self-assessment questionnaires every 4 weeks, photographs, and clinical evaluations were used to rate the efficacy of the treatment. Lim found that the addition of kojic acid to the glycolic acid/hydroquinone gel improved melasma. Specifically, more than half of the melasma cleared in 24 of 40 patients who received the kojic acid formulation, compared with 19 of 40 who received the kojic acid–free gel. Two patients experienced complete clearance, in both cases on the side of the face on which the kojic acid gel was used (Dermatol. Surg. 1999;25:282-4). Two years later, Ferioli and colleagues found that combining hydroquinone and kojic acid exerted a synergistic effect, with an equimolecular distribution achieving the optimal result (Int. J. Cosmet. Sci. 2001;23:333-40).
As a lone therapy for the treatment of melasma, however, kojic acid is a member of the arsenal but is one of the last options typically selected (Dermatol. Clin. 2007;25:337-42), because it may be irritating to the skin (Skin Therapy Lett. 2006;11:1-6; Dermatol. Nurs. 2004;16:401-6, 413-6). It can be effective, though, in patients who do not tolerate the first-line products, particularly hydroquinone (Dermatol. Nurs. 2004;16:401-6, 413-6). Furthermore, combining a topical corticosteroid with kojic acid can reduce the irritant qualities of the fungal derivative (Int. J. Dermatol. 1998;37:897-903; Phytother. Res. 2006;20:921-34). In the experimental setting, kojic acid is regularly used as a reference or positive control to test the skin-whitening potential of new agents.
Antiwrinkle Properties
Other applications of kojic acid have also been considered. In 2001, Mitani and colleagues investigated the potential antiwrinkle activity of kojic acid given the iron-chelating properties of the acid and the known association between chronic photodamage and cutaneous iron. Over 20 weeks, the investigators topically applied kojic acid prior to exposing hairless mice to UV radiation. The agent successfully inhibited wrinkle development, epidermal hyperplasia, lower dermis fibrosis, and increases in upper dermis extracellular matrix components (Eur. J. Pharmacol. 2001;411:169-74).
Skin-Lightening Properties
The primary use for kojic acid in dermatology, though, remains skin whitening. Kojic acid is second only to hydroquinone in terms of effectiveness as a skin-lightening agent in topical, over-the-counter products (Dermatol. Ther. 2007;20:308-13), and is the most popular agent for treating melasma in East Asia (Dermatol. Surg. 1999;25:282-4; Dermatol. Ther. 2007;20:308-13).This makes sense, given the increasing regulatory scrutiny of hydroquinone, which has been banned in Europe and is tightly regulated in Asia, while remaining available, however tenuously, in the United States. Kojic acid is also a sensitizer. Mild facial erythema is the primary adverse effect reported in association with the typically well-tolerated fungal metabolite (Dermatol. Clin. 2007;25:353-62), which has been banned and then permitted to return to the market as a skin-lightening agent (Dermatol. Ther. 2007;20:308-13).
Kojic acid products are typically used twice daily for 1 to 2 months or until the patient achieves the desired results. Unfortunately, kojic acid has reportedly provoked contact allergies and is considered to exhibit a high sensitizing potential (Contact Dermatitis 1995;32:9-13). Because preparations containing a 2.5% concentration of kojic acid have been associated with facial dermatitis, a concentration of 1% has become more common. However, there have also been some reports of sensitization linked to 1% creams (Contact Dermatitis 1995;32:9-13). As kojic acid has also been extensively used in foods, there have been many reports on its oral safety. In addition, injecting kojic acid has the potential to induce convulsions (Regul. Toxicol. Pharmacol. 2001;33:80-101).
Possible Link With Tumor Promotion
Despite the success of kojic acid at 1% concentrations, particularly in Japan, some studies have indicated that longer term use of the agent may engender contact dermatitis and erythema (Skin Therapy Lett. 2004;9:1-3; Contact Dermatitis 1998;39:86-7; Contact Dermatitis 1995;32:9-13). In addition, an association between hepatic tumors in heterozygous p53-deficient mice and the topical application of kojic acid has been identified (Toxicol. Sci. 2003;73:287-93; Dermatol. Clin. 2007;25:353-62). In 2003, Japan’s health ministry ordered the removal of kojic acid from the market over fears, based on animal studies, that the fungal metabolite might cause cancer (Nature 2004;432:938).
In response to such findings and concerns, specifically the link between potential tumor promotion in mouse and rat livers caused by use of kojic acid, Higa and colleagues examined the presence of initiation activity in rat liver and the potential of photogenotoxicity and carcinogenicity in mouse skin in relation to kojic acid. In one of the team’s multiple experiments, a cream containing 1.0% or 3.0% kojic acid was applied twice to the backs of mice in a 24-hour period, and researchers noted that kojic acid failed to induce epidermal cell micronuclei. In addition, a skin carcinogenesis bioassay for initiation-promotion potential revealed the emergence of no skin nodules that were caused by the topical application of 3.0% kojic acid cream to the backs of mice daily for 7 days or five times a week for 19 weeks, administered during either cancer stage. Overall, the investigators concluded that kojic acid posed a minimal risk of photocarcinogenesis in the skin and did not exhibit skin carcinogenesis initiation nor promotion activity. The findings also lent support to the contention that kojic acid is a safe ingredient in cosmeceuticals (J. Toxicol. Sci. 2007;32:143-59). In addition, Lee and colleagues recently reported on derivatives of kojic acid displaying greater efficiency through increased penetration into the skin (Arch. Pharm. (Weinheim) 2006;339:111-4).
Previously, in 2003, Kim and colleagues studied the effects of a stable kojic acid derivative, 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one (Kojyl-APPA), on tyrosinase activity and melanin production. The investigators found that Kojyl-APPA is not a direct inhibitor of tyrosinase, but is enzymatically converted to kojic acid in cells. However, the derivative was found to suppress tyrosinase activity markedly 24 hours after treatment in normal human melanocytes and demonstrated a 30% inhibition of tyrosinase in situ (although not in vitro). The kojic acid derivative also lowered melanin content to 75% of control in melanoma cells and neomelanin production to 43% of control in normal human melanocytes. Notably, Kojyl-APPA had an eightfold greater capacity to permeate the skin than did kojic acid (Chem. Pharm. Bull. (Tokyo) 2003;51:113-6). A kojic acid derivative found to be eight times more potent than kojic acid as a tyrosinase inhibitor was also synthesized in 2006. The compound produced by Lee and colleagues also displayed strong inhibitory activity toward melanin production (Arch. Pharm. (Weinheim) 2006;33:111-4).
It is worth noting that although kojic acid yields greater stability than does hydroquinone, the fungal derivative does have labile oxidative properties, which are enhanced by light and heat exposure. For that reason, the inclusion of kojic acid in cosmetic formulations has been through its dipalmitic ester (as kojic dipalmitate) (Talanta 2008;75:407-1).
Conclusion
The fungal derivative kojic acid has maintained a significant role in the dermatologic armamentarium for 2 decades as a skin-whitening agent and is best used in combination with other depigmenting ingredients, which enhance the overall effect of the formulation and blunt the irritating effects of kojic acid. Recent evidence has allayed fears regarding long-term carcinogenic effects, but as always, research is ongoing to develop newer, safer derivatives.
Dr. Baumann writes the column “Cosmeceutical Critique,” which regularly appears in Skin & Allergy News. She is in private practice in Miami Beach. To respond to this column, or to suggest topics for future columns, e-mail her at sknews@elsevier.com.