Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase

Abstract

Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target for inhibiting hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC) in the millimolar range, and kojic acid showed a weak efficacy (IC > 500 μmol/L). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified Thiamidol (Beiersdorf AG, Hamburg, Germany) (isobutylamido thiazolyl resorcinol), which had an IC of 1.1 μmol/L. In contrast, Thiamidol only weakly inhibited mushroom tyrosinase (IC = 108 μmol/L). In melanocyte cultures, Thiamidol strongly but reversibly inhibited melanin production (IC = 0.9 μmol/L), whereas hydroquinone irreversibly inhibited melanogenesis (IC = 16.3 μmol/L). Clinically, Thiamidol visibly reduced the appearance of age spots within 4 weeks, and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of Thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies.

Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma

“…However, the clinical efficacy of current tyrosinase inhibitors is limited due to the fact that they were typically selected based on their ability to inhibit mushroom tyrosinase (Chang, 2009;Lee et al, 2016). In recent studies, Thiamidol was characterized as an especially potent inhibitor of human tyrosinase (Mann et al, 2018a(Mann et al, , 2018b. In vitro, Thiamidol was superior to frequently used inhibitors of hyperpigmentation such as arbutin, kojic acid, and hydroquinone.…”

“…In addition, there was no post-study follow-up on the subjects after the treatment ended, which may have yielded valuable information. The treatment period of 12 weeks was chosen based on experience from preceding studies (Mann et al, 2018a). Our previous studies with other tyrosinase inhibitors showed that it takes several weeks for hyperpigmentation to return to baseline after treatment and no rebound effect was observed (Kolbe et al, 2013).…”

“…Thus, it is evident that an effective and safe topical inhibitor of human skin hyperpigmentation is lacking. Recently, more than 50,000 compounds were screened for their ability to inhibit a recombinant human tyrosinase (Cordes et al, 2013) and Thiamidol (isobutylamido-thiazolyl-resorcinol) was identified as an especially potent inhibitor of human tyrosinase (Mann et al, 2018a(Mann et al, , 2018b. In vitro, Thiamidol was superior to frequently used inhibitors of hyperpigmentation, such as arbutin, kojic acid, and hydroquinone.…”

“…In vitro, Thiamidol was superior to frequently used inhibitors of hyperpigmentation, such as arbutin, kojic acid, and hydroquinone. In vivo, Thiamidol reduced the visibility of solar lentigines at concentrations as low as 0.1% within 4 weeks of treatment (Mann et al, 2018a). Therefore, an exploratory clinical study was conducted to assess the efficacy and tolerance of a formulation containing 0.2% Thiamidol, and to compare it to a formula comprising 2.0% hydroquinone, when used by women with mild to moderate melasma.…”

Kojic acid derivatives as potential anticancer agents: Synthesis and cytotoxic evaluation on A375 human malignant melanoma cells

“…For the stated reasons treatment of hiperpigmentation is an attractive target for the development of new depigmenting agents with further application in pharmacological and cosmetic fields. Currently, the safest and the most effective way to treat cutaneous hyperpigmentation is said to be reducing melanin production by inhibiting tyrosinase activity which is the critical rate-limiting enzyme [7].…”