Kojic acid (KA) is a known byproduct of fungal metabolism, mainly Aspergillus and Penicillium. It can be found naturally in a variety of foods such as soybean paste, soy sauce, and even sake. Furthermore, it has been a food additive for many years working to prevent premature browning of organic food sources (Burdock, Soni, & Carabin, 2001). The versatility of KA is quite intriguing. For instance, certain studies have shown it to be a possible agent to indirectly treat parasitic infections such as leishmaniasis, which can manifest with mucosal, visceral, or cutaneous pathology (Rodrigues et al., 2014). Cosmetically, KA has also been studied as a treatment for wrinkles in the skin because of its known free radical scavenging capabilities (Goncalez, Correa, & Chorilli, 2013). However, the most recognized current use of KA lies in the skin lightening realm of dermatology. KA has been used in the treatment of melasma, a predominantly female, idiopathic, hyperpigmentation disorder that occurs mainly on the face (Monteiro et al., 2013). Pregnancy, estrogen exposure, ultraviolet radiation, and family history have all shown some correlation with melasma, but no cause-and-effect relationship has ever clearly been shown (Lim, 1999). In addition to melasma, KA has been proposed to aid in the treatment of postinflammatory hyperpigmentation. Postinflammatory hyperpigmentation is a darkening of the skin that takes place after inflammation or injury. In theory, KA would work for this indication; however, no significant studies have shown true benefits (Davis & Callender, 2010).
MECHANISM OF ACTION
Chemically known as 5-hydroxymethyl-4H-pyran-4-one, KA works to inhibit tyrosinase by chelating copper (Cu2) at the enzyme's active site (Davis & Callender, 2010; Draelos, 2007). Tyrosinase is the rate-limiting enzyme in the synthesis of melanin and is responsible for converting L-tyrosine to L-3,4-dihydroxyphenylalanine (Goldstein, Goldstein, & Callender, 2014). Typically, hypopigmenting agents can be classified depending on which step of melanogenesis they work to disrupt. Depending on the agent, they can work before, during, or after melanogenesis. KA is specified as a skin lightening agent that works during the actual synthesis of melanin. Historically, tyrosinase inhibitors have been shown to be the most effective skin lightening agents. However, KA tends to be on the milder end of the skin lightening activity spectrum, as compared with the current standard of care agent, hydroquinone (Kim, Choi, Kim, & Park, 2012). Decreasing melanogenesis is an effective treatment strategy for the patient with typical hyperpigmentation.
Besides chelating Cu2+ at the active site of tyrosinase, KA has also been shown to bind ions released from other transition metals such as ferric (Fe3+) iron. In one particular study, the chelation of free radicals by KA is showing great promise in combating the appearance of skin aging and wrinkling (Goncalez et al., 2013). Although presumably useful, the mechanism in which KA works against leishmaniasis is not fully understood. It is hypothesized that KA has an indirect action of macrophage activation that hastens the clearance of the infection (Rodrigues et al., 2014).
DOSING AND ADMINISTRATION
KA is available over the counter (OTC) in a 1%-4% concentrated gel or cream (Davis & Callender, 2010). Typically, KA is combined with 2% hydroquinone in an alpha-hydroxy acid gel base. The melasma area severity index was used to assess the efficacy of varied treatments in a recent randomized, single-blinded, comparative study that compared KA 1% cream, hydroquinone 2% cream, and betamethasone valerate 0.1% cream in patients with melasma. KA 1% cream used in conjunction with hydroquinone 2% cream showed greater clinical efficacy than any other combination of substances containing KA 1% cream (Deo, Dash, Sharma, Virmani, & Oberai, 2013).
In addition to the previous study, another separate split-face study analyzed 40 Chinese women experiencing melasma. It compared the use of a mixture of KA 2%, hydroquinone 2%, and glycolic acid 10% with a separate preparation containing only hydroquinone 2% and glycolic acid 10%. The results showed that 24 of 40 women in the study had greater improvement on the side with mixture of KA 2%, hydroquinone 2%, and glycolic acid 10%, as compared with only 19 of 40 on the side containing only hydroquinone 2% and glycolic acid 10%. However, it should be specified that close to 50% of the study participants failed to notice a difference between the two sides (Lim, 1999). These studies point at a possible indication for a combined treatment when considering KA for a therapeutic treatment of melasma.
ADVERSE EFFECTS OF KA
KA, like many topical medications, has the ability to cause local irritation to the original application site. A burning sensation, as well as acneiform eruptions, occurred in one study after the application of KA 1% cream (Deo et al., 2013). It has also been reported that KA can be a strong sensitizer (Draelos, 2007; Goldstein et al., 2014). According to a recent case report, a patient experienced erythematous hyperpigemented areas on the arms and legs that were followed up with a positive patch test to 1% KA (Garcia-Gavin, Gonzalez-Vilas, Fernandez-Redondo, & Toribio, 2010).
ALTERNATIVE MEDICATIONS AND TREATMENT
The current standard of care for the initial treatment of hyperpigmentation involves the use of tyrosinase inhibitors. Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, is a tyrosinase inhibitor available in 2%-4% concentrations and remains the current gold standard in terms of efficacy for hyperpigmentation therapy within the United States (Draelos, 2007). However, as already presented in this report, combined therapy with KA may help augment treatment when hydroquinone does not result in complete resolution (Lim, 1999). Major drawbacks to hydroquinone compared with KA include more serious contact dermatitis and a well-defined increased risk of developing ochronosis (Goldstein et al., 2014).
Azelaic acid (AA) is another option for the treatment of hyperpigmentation disorders. It is a nonphenolic naturally occurring competitive inhibitor of tyrosinase (Goldstein et al., 2014). Fifteen percent of AA gel has been shown to have a similar skin lightening action as compared with hydroquinone with a much safer side effect profile for the treatment of melasma. AA also has a propensity to only seek out abnormal melanocytes to inhibit. The previous fact indicates that AA is more useful for conditions such as lentigo maligna and lentigo maligna melanoma. Furthermore, it disrupts DNA synthesis in some cases as a secondary mechanism of action (Draelos, 2007).
Mequinol is another phenolic competitive tyrosinase inhibitor similar to KA. Common side effects include burning, scaling, and intense pruritis (Goldstein et al., 2014). Long-term depigmentation is a risk that must be weighed when considering mequinol for the treatment of melasma. Very frequently, mequinol 2% concentration is combined with 0.01% tretinoin for improved skin lightening (Draelos, 2007). Although tretinoin (all-trans retinoic acid) has been shown to improve melasma through an increase in keratinocyte turnover, melanosome transfer, and drug penetration, it is still seldomly used as an isolated treatment for melasma (Goldstein et al., 2014).
The use of chemical peels and laser treatment should only be implemented in refractory cases of severe melasma. Chemical peels injure the skin in a moderately controlled manner to promote exfoliation and the generation of new, postexfoliation, improved skin. Laser treatment for melasma has yet to be perfected and results in erythema, scaling, dryness, stinging or burning, edema, and hypopigmentation or hyperpigmentation (Goldstein et al., 2014).
CONCLUSION
The unique applications of KA make it an intriguing drug with useful indications in the specialty of dermatology. KA is certainly a good option when considering an OTC initial treatment option for mild-to-moderate melasma or general skin hyperpigmentation, mainly because of its relatively benign side effect profile. However, care should also be taken in patients who are prone to contact sensitization, as this has been presented as a possible adverse effect of KA on numerous occasions. In addition, for refractory melasma, it is important to consider the option of KA as an additional tool in the recipe for combination therapy. Although KA is available OTC, it is important to have a dermatologist evaluate each patient with hyperpigmentation or melasma. If deemed appropriate by the dermatologist, KA can be combined with hydroquinone, AA, mequinol, and topical retinoids to provide an enhanced depigmentation result. Further studies will be needed to ascertain a cause-and-effect relationship between KA and the proposed benefits it presents through transition metal chelation, beyond its inhibitory effect on tyrosinase. This Aspergillus metabolite should not be disregarded in any case where a treatment for hyperpigmentation is sought.
REFERENCES