Inhibition of Tyrosinase and Melanogenesis by Carboxylic Acids: Mechanistic Insights and Safety Evaluation

It is well established that certain carboxylic acid compounds can effectively inhibit tyrosinase activity. This study investigated the mechanisms by which four carboxylic acid compounds-3-phenyllactic acid, lactic acid, L-pyroglutamic acid, and malic acid-inhibit tyrosinase and melanogenesis. IC₅₀ values for mushroom tyrosinase inhibition ranged from 3.38 to 5.42 mM, with 3-phenyllactic acid (3.50 mM), lactic acid (5.42 mM), and malic acid (3.91 mM) exhibiting mixed-type inhibition, while L-pyroglutamic acid (3.38 mM) showed competitive inhibition, as determined by enzymatic kinetic analysis. Additionally, the acidification effects of lactic acid, L-pyroglutamic acid, and malic acid contributed to the reduction in tyrosinase activity. Furthermore, all four carboxylic acid compounds effectively inhibited DOPA auto-oxidation (IC₅₀ = 0.38-0.66 mM), ranking in potency as follows: malic acid (0.38 mM) > lactic acid (0.57 mM) > 3-phenyllactic acid (0.63 mM) > L-pyroglutamic acid (0.66 mM). These compounds also demonstrated a dose-dependent reduction in melanin production in B16-F10 cells. Proteomic analysis further revealed that these compounds not only inhibit key proteins involved in melanin synthesis, such as tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2, but also potentially modulate other genes associated with melanogenesis and metabolism, including Pmel, Slc45a2, Ctns, Oca2, and Bace2. Network toxicology analysis indicated that these four compounds exhibit a low risk of inducing dermatitis. These findings suggest that these compounds may indirectly regulate melanin-related pathways through multiple mechanisms, highlighting their potential for further applications in cosmetics and pharmaceuticals.