Tyrosinase inhibitors in skincare: what are they and why are they in popular demand?

By Esha Kulkarni

The skincare industry is currently on the rise due to celebrity promotions, social media influencers, and commercials. Awareness of specific key ingredients in skincare such as salicylic acid, niacinamide, ascorbic acid, and hyaluronic acid have been the talk of the show lately. The basic mechanisms by which these key ingredients work have been well studied and publicised in certain populations. 

But firstly, it is important to understand why skincare regimes have been prioritised in the recent years, and why people actively seek out to buy specific skincare products. Surveys conducted by several companies show that 18% of people seek skincare products to address skin-specific issues, the most common issue being acne, especially during puberty. However, in contrast, epidemiological studies show that racial/ethnic groups with darker skin consult dermatologists to help tackle issues such as post-inflammatory hyperpigmentation as it tends to affect them with more severity and can have negative psychological impacts as well (Davis & Callender, 2010). Scarring from acne, can get progressively worse, with prolonged sun exposure. Tyrosinases, an enzyme, distributed in organisms is found to be the underlying cause for this increase in melanogenesis, possibly leading to various types of hyperpigmentation. This has stimulated researchers to isolate and identify inhibitors suitable for downregulating the effects of tyrosinase, which is an attractive pathway for treating several hyperpigmentation issues, possibly revolutionising the cosmeceutical industry. 

Tyrosinase is a multi-copper enzyme that is involved in the biosynthesis of melanin. It is also a membrane bound glycoprotein found in a melanosome, or a “melanin factory”, since it is the site of melanin production (Pillaiyar et al., 2017). Tyrosinase catalyses two reactions steps, one of them being a rate-limiting step, which ultimately results in the production of melanin. Firstly, it helps catalyse phenols to catechol, and then converts catechol to quinones by oxidizing it (Chuan Chen et al., 2015).

Since tyrosinases are involved in a crucial stage of melanogenesis, certain tyrosinase inhibitors have been developed in research labs throughout the years, with varying degree of efficacy. This article will comprehensively review some of the most common topical tyrosinase inhibitors and discuss why there are recent clinical and industrial demands for tyrosinase inhibitors. 

Before we dig deep into the different types of topical tyrosinase inhibitors available on the market, it is crucial to have a brief overview of the proposed mechanisms of tyrosinase inhibitions. There are several types of tyrosinase inhibitors, but the ones to look into are specific tyrosinase inactivators. These molecules are also called “suicide” inactivators. In layman terms, the enzymes bind to an “inhibitor” which has in fact been modified into a substrate. This stimulates the enzyme to irreversibly inhibit its own catalytic activity hence it inadvertently “kills itself” (Zolghadri et al., 2019). This has been deemed to be an area of pharmacological importance in treating hyperpigmentation.

Moving on to the some of the topical tyrosinase inhibitors, it is ideal to start off by looking into the infamous hydroquinone, previously described as the “gold standard” treatment of hyperpigmentation in the cosmeceutical/skincare industry. Hydroquinone acts as the above mentioned “suicide inhibitor” which ultimately competitively inhibiting melanin synthesis (Sarkar et al., 2013). The free radicals released during this reaction also is known to destroy the melanosomes and melanocytes, hence why it was the benchmark of hyperpigmentation treatment. Clinical studies have reported that patients responded spectacularly to 2% hydroquinone synthesis (Sarkar et al., 2013). However, with all the positives, came a few negatives. There were reports of adverse side effects some including, exogenous orchronosis (blue-black pigmentation on skin), nail pigmentation (yellow nails), low elasticity of the skin (possibly due to a loss of collagen in skin), and the ability to heal wounds was also impaired. However, what set the possible downfall of hydroquinone was when study models found hydroquinone to damage DNA and may be carcinogenic synthesis (Sarkar et al., 2013). This led to the European Union (EU), for example, completely banning the use of hydroquinone as an ingredient early on, in 2001 (Arrowitz et al., 2019). 2% hydroquinone is still however, available for sale over the counter in the United States, but the Food and Drug Administration (FDA) is still considering banning its synthesis completely (Sarkar et al., 2013). However, one should take into consideration that in most studies, hydroquinone was administered either orally or parentally and not topically. Nevertheless, the chronic side effects listed above, related to topical use should be heavily considered. This exacerbated the need for researchers to find an alternative, effective and safe topical tyrosinase inhibitor leading to the popular demand in skincare industry.  

The two most prevalent tyrosinase inhibitors widely used in the markets currently are kojic acid and arbutin, even offered by the famous skincare company “The Ordinary”. Kojic acid is natural, as it is derived from hydrophilic fungal products, for example, Acetobacter, Aspergillus, and Penicillium (Sarkar et al., 2013). It has antioxidant properties and inhibits the production of tyrosinase. Some studies have suggested that patients might respond better to kojic acid in comparison to hydroquinone. 

Arbutin is probably the most prescribed hyperpigmentation treatment in the skincare industry currently. Interestingly, arbutin is a plant product, derived from dried leaves of blueberry, cranberries, and pear trees. Arbutin inhibits tyrosinase competitively in non-toxic concentrations and inhibits melanosome maturation. However, studies have shown arbutin is suitable for treating milder forms of hyperpigmentation hence can be less effective than kojic acid or hydroquinone. 

Since there is plenty of research on acne-related products and treatments, the skincare community and cosmeceutical industries are now slowly shifting their focus on treating hyperpigmentation as it is causes long-lasting damage and affects a large population that face prolonged sun exposure, i.e., tropical areas. Tyrosinase inhibitors are still under the spotlight, and after the “hydroquinone ban”, researchers have been keener that ever to re-modify existing tyrosinase inhibitors and are on the lookout for new ones. 

References:

Arrowitz, C., Schoelermann, A. M., Mann, T. & Jiang, L. (2019) Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma. Journal of Investigative Dermatology. 139 (8), 1691-1698. Available from: doi:10.1016/j.jid.2019.02.013.

Chuan Chen, W., Sheng Tseng, T. & Hsiao, N.-W. (2015) Discovery of Highly Potent Tyrosinase Inhibitor, T1, with Significant Anti-Melanogenesis Ability by zebrafish in vivo Assay and Computational Molecular Modeling. Scientific Reports. 5. Available from: doi:10.1038/srep07995. 

Davis, E. C. & Callender, V. D. (2010) Postinflammatory Hyperpigmentation. The Journal of Clinical and Aesthetic Dermatology. 3 (7), 20-31. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921758/ [Accessed 16th May 2021].

Pillaiyar, T., Manickam, M. & Namasivayam, V. (2017) Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry. 32 (1), 403-425. Available from: doi:10.1080/14756366.2016.1256882. 

Sarkar, R., Arora, P. & Garg, K. V. (2013) Cosmeceuticals for Hyperpigmentation: What is Available? Journal of Cutaneoous and Aesthetic Surgery.  6 (1), 4-11. Available from: doi:10.4103/0974-2077-110089.

Zolghadri, S., Bahrami, A. & Hassan Khan, M. T. (2019) A comprehensive review on tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry.  34 (1), 279-309. Available from: doi:10.1080/14756366.2018.1545767.

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