Kojic Acid

Kojic acid, a natural ingredient formed as a byproduct during the manufacture of many Japanese foods, is not as effective as hydroquinone in lightening the skin, but also does not have the latter's laundry list of warnings.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

C

Melasma treatment

Strong

Clears facial melasma very effectively especially when combined with hydroquinone, with which it has a synergistic effect.

D

Skin lightening

Moderate

Lightens the skin by chelating copper at the active site of tyrosinase, the enzyme involved in melanin synthesis, and thereby inhibiting its activity.

D

Wrinkle treatment

Moderate

Thought to prevent wrinkling induced by UV radiation via its iron-chelating and radical-scavenging abilities.

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Scientific Research


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Table of contents:

1. Sources

Kojic acid is a natural substance produced by many species of fungi, especially Aspergillus oryzae, which is known in Japan as koji. It has a long history of consumption, because it is produced during the fermentation process in the production of a number of foods including miso (soybean paste), shoyu (soy sauce) and sake.[1][2]

2. Bioavailability

Studies on rats have shown that kojic acid is rapidly absorbed after dermal administration, with occlusion enhancing penetration.[3] Additionally, copaiba oil and the use of nanotechnology-based drug delivery systems also promote permeation.[4][5]

In a study on 6 Japanese women, applying 1% of a koijc acid formulation on the cheeks led to detectable plasma concentrations of kojic acid. Repeated exposure also appears to increase the levels of kojic acid in the blood, and hence result in higher systemic exposure, than after a single application.[3]

3. Effects on the skin

3.1 Lightening effect

Kojic acid inhibits the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis[6] mainly by chelating copper at the active site of the enzyme,[7] though its anti-melanogenic activity is also associated with increased IL-6 production.[8]

The effect of kojic acid on cultures of skin cells is less clear. One study showed that despite being a potent inhibitor of mammalian tyrosinase, it was unable to reduce pigmentation in intact melanocytes.[9] 2 other studies investigated the melanin content of melanocytes co-cultured with keratinocytes, and one found that the addition of kojic acid did not have any effect,[10] while the other found a 26% decrease in melanin content compared to the control.[11]

In addition, kojic acid significantly reversed the enhanced pigmentation in the epidermal cells of human skin explants exposed to UV light.[12] A topical product containing kojic acid, emblica extract and glycolic acid was also as effective as 4% hydroquinone cream in lightening the skin of 80 patients with mild to moderate facial dyschromia in a double-blind study.[13]

3.2 Melasma treatment

Melasma is a common acquired cause of facial hyperpigmentation that is aggravated by sunlight, pregnancy and the use of birth control pills.[14]

When a cream containing 1% kojic acid was applied daily to 20 melasma patients, a mean 59% improvement in Melasma Area and Severity (MASI) score was observed after 12 weeks.[15] In a split-face study, 2 similar formulations of glycolic acid + hydroquinone and glycolic acid + kojic acid were applied on each half of the face of 39 patients, and were found to be equally effective in reducing pigmentation.[14]

Kojic acid also has a synergistic effect when combined with hydroquinone;[16] in a study on 40 Chinese women, 2% kojic acid in a gel containing 2% hydroquinone and 10% glycolic acid improved epidermal melasma to a greater extent than a similar gel free of kojic acid.[17] Similarly, 1% kojic acid combined with 2% hydroquinone was more effective than 1% kojic acid alone or other combinations of 1% kojic acid, 2% hydroquinone and/or 0.1% betamethasone valerate in reducing melasma area and severity.[15]

A cream containing 0.75% kojic acid and 2.5% ascorbic acid, however, was inferior to 4% hydroquinone cream in treating facial melasma in another trial.[18]

3.3 Anti-wrinkle effect

Iron in the skin is thought to play a key role in photoaging, as it catalyses the generation of reactive oxygen species[19] which can contribute to photodamage and wrinkling. Because kojic acid possesses the ability to chelate iron and scavenge radicals, its anti-wrinkling activity has been evaluated in a study on hairless mice. Chronic exposure to solar-simulated UV irradiation for 20 weeks induced wrinkling, epidermal hyperplasia, conversion of adipose tissue into fibrous tissue in the lower dermis, and an increase in the chondroitin/dermatan sulfate content in the upper dermis. Kojic acid prevented wrinkling when applied to the skin of the mice prior to UV irradiation however, and this anti-wrinkle effect was associated with its strong suppression of the UV-induced alterations in the dermis.[20]

4. Side Effects

4.1 Skin irritation

Kojic acid can be irritating to the skin. It is considered to have a high sensitizing potential, and frequently provokes contact allergies or contact dermatitis.[21][22][23][24] As a result, it is considered safe for use in cosmetics only up to a concentration of 1%.[25]

4.2 Potential carcinogenicity

Chronic administration of kojic acid through the diet has been associated with increased hepatocellular adenomas in mice[26] and increased thyroid follicular carcinomas in rats,[27], giving rise to fears over its cancer-causing potential. A more recent study, however, concluded that 3% kojic acid cream does not initiate nor promote skin carcinogenesis, as it did not induce micronuclei in mouse epidermal cells or lead to the formation of skin nodules when applied to the back of mice.[28] Moreover, systemic exposure to kojic acid in humans after topical application is estimated to be in the range of 0.03-0.06 mg/kg/day, a level that is not thought to pose significant risk of genotoxicity or toxicity to consumers.[29] These findings lend support to the contention that kojic acid is a safe ingredient when used in cosmetics.

Scientific References


  1. Burdock GA, Soni MG, Carabin IG. Evaluation of health aspects of kojic acid in food. Regul Toxicol Pharmacol. (2001)
  2. Bentley R. From miso, saké and shoyu to cosmetics: a century of science for kojic acid. Nat Prod Rep. (2006)
  3. Scientific Committee on Consumer Safety. Opinion on Kojic Acid. SCCS. (2012)
  4. Oliveira RVM, et. al. In vitro evaluation of copaiba oil as a kojic acid skin enhancer. BJPS. (2010)
  5. Gonçalez ML, Corrêa MA, Chorilli M. Skin delivery of kojic acid-loaded nanotechnology-based drug delivery systems for the treatment of skin aging. Biomed Res Int. (2013)
  6. Cabanes J, et. al. Kojic acid, a cosmetic skin whitening agent, is a slow-binding inhibitor of catecholase activity of tyrosinase. J Pharm Pharmacol. (1994)
  7. Chang TS. An updated review of tyrosinase inhibitors. Int J Mol Sci. (2009)
  8. Choi H, et. al. Kojic acid-induced IL-6 production in human keratinocytes plays a role in its anti-melanogenic activity in skin. J Dermatol Sci. (2012)
  9. Curto EV, et. al. Inhibitors of mammalian melanocyte tyrosinase: in vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors. Biochem Pharmacol. (1999)
  10. Lei TC, et. al. A melanocyte-keratinocyte coculture model to assess regulators of pigmentation in vitro. Anal Biochem. (2002)
  11. Springer M, Engelhart K, Biesalski HK. Effects of 3-isobutyl-1-methylxanthine and kojic acid on cocultures and skin equivalents composed of HaCaT cells and human melanocytes. Arch Dermatol Res. (2003)
  12. Vie K, et. al. Ultrastructural assessments of the melanosome distribution patterns and pigmentation features in human epidermal cells after UV irradiation and kojic acid treatment. Int J Cosmet Sci. (2009)
  13. Draelos ZD, et. al. Evaluation of a kojic acid, emblica extract, and glycolic acid formulation compared with hydroquinone 4% for skin lightening. Cutis. (2010)
  14. Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg. (1996)
  15. Deo KS, et. al. Kojic Acid vis-a-vis its Combinations with Hydroquinone and Betamethasone Valerate in Melasma: A Randomized, Single Blind, Comparative Study of Efficacy and Safety. Indian J Dermatol. (2013)
  16. Ferioli V, et. al. New combined treatment of hypermelanosis: analytical studies on efficacy and stability improvement. Int J Cosmet Sci. (2001)
  17. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. (1999)
  18. Monteiro RC, et. al. A Comparative Study of the Efficacy of 4% Hydroquinone vs 0.75% Kojic Acid Cream in the Treatment of Facial Melasma. Indian J Dermatol. (2013)
  19. Kitazawa M, Iwasaki K, Sakamoto K. Iron chelators may help prevent photoaging. J Cosmet Dermatol. (2006)
  20. Mitani H, et. al. Prevention of the photodamage in the hairless mouse dorsal skin by kojic acid as an iron chelator. Eur J Pharmacol. (2001)
  21. Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermatitis. (1995)
  22. Serra-Baldrich E, Tribó MJ, Camarasa JG. Allergic contact dermatitis from kojic acid. Contact Dermatitis. (1998)
  23. Mata TL, Sanchez JP, De La Cuadra Oyanguren J. Allergic contact dermatitis due to kojic acid. Dermatitis. (2005)
  24. García-Gavín J, et. al. Pigmented contact dermatitis due to kojic acid. A paradoxical side effect of a skin lightener. Contact Dermatitis. (2010)
  25. Burnett CL, et. al. Final report of the safety assessment of Kojic acid as used in cosmetics. Int J Toxicol. (2010)
  26. Takizawa T, et. al. Hepatocellular tumor induction in heterozygous p53-deficient CBA mice by a 26-week dietary administration of kojic acid. Toxicol Sci. (2003)
  27. Ota Y, et. al. A 55-week chronic toxicity study of dietary administered kojic acid (KA) in male F344 rats. J Toxicol Sci. (2009)
  28. Higa Y, et. al. Kojic acid -absence of tumor-initiating activity in rat liver, and of carcinogenic and photo-genotoxic potential in mouse skin. J Toxicol Sci. (2007)
  29. Nohynek GJ, et. al. An assessment of the genotoxicity and human health risk of topical use of kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Food Chem Toxicol. (2004)