The underlying study examines the medical application of kojic acid by evaluating a wide range of studies dealing with the biological activity of kojic acid and its derivatives and shedding light on their mechanisms of action. In particular, our study summary highlights the findings on the use of kojic acid as a depigmenting agent.
In addition to its depigmenting properties, the anti-oxidative, anti-microbial, anti-inflammatory, radioprotective and anti-convulsive properties of kojic acid and its derivatives can also be used medicinally. The depigmenting activity of kojic acid is attributed to its molecular structure: after cell penetration, it binds to the active center of the tyrosinase enzyme. Furthermore, factors of melanin synthesis and leukocyte modulation are regulated and copper ions are chelated. Kojic acid also acts as a free radical scavenger.
Koji acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) is an organic acid first isolated in 1907, which is obtained by fermentation from various fungal strains, such as Aspergillus and Penicillium. It is often used as an alternative to hydroquinone as the latter, despite its popularity, can cause problems with safe use such as permanent depigmentation.
A 2015 study showed anti-dermatophytic, anti-mycobacterial, anti-oxidative and anti-tyrosinate effects of Mannich bases developed from koji acids.
A depigmenting property of kojic acid was detected in 25 out of 63 of the studies analyzed.
The main mechanism of depigmentation is the inhibition of tyrosinase, the key enzyme in melanin synthesis. The substrate of tyrosinase is copper, which is chelated by kojic acid in the active center of the molecule. Copper also suppresses the tautomerization of DOPA to 5,6-dihydroxyindole-2-carboxylic acid. Furthermore, leukocyte modulation and free radical scavenging are also involved in the depigmentation mechanism of kojic acid.
Since free radicals and reactive oxygen species (ROS) can also cause melanin synthesis, the anti-oxidative activity of kojic acid also plays a role in controlling melanin synthesis. Mechanisms that do not act on tyrosinase have also been reported in the literature. These findings suggest that upregulation of IL-6 production in cerationocytes causes a reduction in melanogenesis in melanocytes, which in turn suggests an interaction between those cells involved in melanin synthesis.
Furthermore, various studies have described a reduction in melanogenesis regulators in the melanocytes. This suppressed the expression of tyrosinase as well as that of 5,6-dihydroxyindole-2-carboxylic acid oxidase (tyrosinase-related protein 1, also known as TYRP 1) and L-dopachrome tautomerase (tyrosinase-related protein 2, also known as TYRP 2)
Tyrosinase inhibition studies were conducted in 19 of the 25 studies analyzed. Of the 25 studies that evaluated depigmentation activity, only six studies did not investigate tyrosinase inhibition. In these studies, the melanin content or in silico methods were used instead to determine the depigmentation activity. The activity of koji-acid-amino acid-amide metal complexes was evaluated in a Mel-Ab cell line. Coordination with the metals increased lipophilicity and thus skin permeation. This resulted in a reduction of the melanin content in the melanocytes.
A co-culture consisting of melanocytes and keratinocytes was used to analyze the cytokine secretion profile caused by kojic acid. The production of cytokine was increased and an increase in the production of interleukin-6 (IL-6) in keratinocytes caused a decrease in melanogenesis in melanocytes. This suggests an interaction between the corresponding cells and the signaling pathway of depigmentation, in which tyrosinase is not involved.
One of the clinical studies analyzed investigated the tolerability of melasma treatment with kojic acid alone, a combination of 1% kojic acid with 2% hydroquinone or 0.1% betamethasone, or with both substances in the concentrations mentioned. Side effects of the formulation such as erythema, skin burning and itching were evaluated on a scale of 1 to 3. Of the 80 study participants divided into four groups, only 3 study participants reported a burning sensation on the skin. One was from the study group that used kojic acid alone and the other two were from the group that used kojic acid and hydroquinone together. In the study, a concentration of 1% kojic acid was considered safe for topical application in the treatment of melasma.
Conclusion
The studies examined confirm the anti-bacterial, anti-fungal and anti-inflammatory effect of kojic acid, which also acts as a free radical scavenger. Kojic acid is also suitable as an anti-ageing agent as it has an anti-oxidative effect. The underlying study concludes that kojic acid and its derivatives cover many possible areas of application in the field of cosmetics.
Underlying study:
Capp Zilles, J. et al.: Biological activities and safety data of kojic acid and its derivatives: A review; in: Experimental Dermatology. 2022;31:1500-1521.