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).