Swertiajaponin inhibits skin pigmentation by dual mechanisms to suppress tyrosinase

Abstract

Many skin-whitening compounds target tyrosinase because it catalyzes two rate-limiting steps in melanin synthesis. Although many tyrosinase inhibitors are currently available for a skin–whitening purpose, undesirable adverse effects are also reported. Thus, numerous efforts have been made to develop safer tyrosinase inhibitors from natural products. In line with this, we tested fifty flavonoids, a group of naturally occurring antioxidants and metal chelators, and screened swertiajaponin as the strongest tyrosinase inhibitor in cell-free experiments. Swertiajaponin did not show cytotoxicity in B16F10, HaCat, and Hs27 cells and exhibited strong anti oxidative activity in experiments using the cell-free system and B16F10 cells. It markedly inhibited αMSH- or UVB-induced melanin accumulation in B16F10 cells and suppressed skin pigmentation in a human skin model. As underlying mechanisms, in silico and Lineweaver-Burk plot analyses exhibited that swertiajaponin may directly bind to and inhibit tyrosinase activity by forming multiple hydrogen bonds and hydrophobic interactions with the binding pocket of tyrosinase. In addition, western blotting results indicated that swertiajaponin inhibited oxidative stress-mediated MAPK/MITF signaling, leading to decrease in tyrosinase protein level. Together, swertiajaponin suppresses melanin accumulation by inhibiting both activity and protein expression levels of tyrosinase. Thus, it would be a novel additive for whitening cosmetics.

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…At present, though a wide range of tyrosinase inhibitors from natural and synthetic sources have been reported, only a few of them, in addition to being effective, are known as safe compounds. No significant advances concerning toxicity issues of tyrosinase inhibitors seem to emerge from the literature survey carried out for this review, the relevant papers just reporting the results of in vitro cytotoxicity experiments [49,52,75,81,95,126,129,[131][132][133]136,137,147,163,[176][177][178]184,185,192,198,202,203,207,210,212,214,215,239,240,242,245] and only a few of in vivo experiments on zebrafish [130,206,209]. Therefore, it is essential to examine the efficacy and safety of inhibitors by checking e.g., whether or not the candidate inhibitor is substrate of tyrosinase being modified on exposure to the enzyme.…”

“…Several inhibition mechanisms have been reported for the tyrosinase inhibitors described above, highlighting the importance of key structural moieties as responsible for the observed effects. As an example, in silico analysis showed that the flavonoids spinosin and swertiajaponin act as competitive inhibitors of the enzyme by binding to the active site through hydrogen bonding and hydrophobic interactions [212,214], as is the case also for condensed tannins from different sources based on molecular docking [96,98,99]. Chelation of copper ions by adjacent hydroxyl groups on the B ring has also been suggested as a feasible inhibition mechanism for proanthocyanidins [101,102,106].…”

“…Most of these studies used B16 murine melanoma cell lines as a model [52,55,75,85,95,96,99,114,122,123,[127][128][129][132][133][134][135]138,139,151,153,155,163,, although some papers using zebrafish as an in vivo whole animal model have also been published [55,116,206]. As to the human sources, data on inhibition of human recombinant or purified tyrosinase [9,207], human melanoma cells [130,136], normal human melanocytes [208][209][210][211], or human skin models consisting of reconstructed three-dimensional human epidermis [212][213][214][215] have been published (Figure 21). The results of clinical trials have also been reported for well recognized skin depigmenting agents [216,217] such as thiamidol, that, as stated also above, is one of the most striking examples of a pigmentation inhibitor exhibiting significant higher activity on human than on mushroom tyrosinase [9,218...…”

“…Several inhibition mechanisms have been reported for the tyrosinase inhibitors described above, highlighting the importance of key structural moieties as responsible for the observed effects. As an example, in silico analysis showed that the flavonoids spinosin and swertiajaponin act as competitive inhibitors of the enzyme by binding to the active site through hydrogen bonding and hydrophobic interactions [212,214], as is the case also for condensed tannins from different sources Of course, care should be taken when cellular or in vivo models are considered, since several alternative or additional biochemical mechanisms can be operative, involving e.g., tyrosinase expression and interference with the complex signaling pathways in melanogenesis, which could result in melanin reduction as well. As an example, it has been reported that both ferulic and caffeic acid inhibited melanin production in B16 melanoma cells, but ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed in the case of caffeic acid [177].…”

Recent Trends in Controlling the Enzymatic Browning of Fruit and Vegetable Products

“…Peer Apple juice Inhibited PPO activity [36,37] Cysteine hydrochloride [29]. The anti-browning effects of antioxidants rely on environmental factors including temperature, pH, light, and composition of the atmosphere [30].…”