Tranexamic Acid Ameliorates Skin Hyperpigmentation by Downregulating Endothelin-1 Expression in Dermal Microvascular Endothelial Cells.

Background: Although reports suggest that tranexamic acid (TXA) has clinical benefits for melasma patients by oral, intralesional and topical treatment, the optimal route of TXA therapy and the underlying mechanism involved remain poorly defined.

Objective: To compare the skin lightening effect between oral TXA and topical TXA and to dissect the molecular mechanisms using ultraviolet B (UVB)-induced hyperpigmentation mouse model, ex vivo cultured human skin explant, and cultured melanocytes (MCs) and endothelial cells.

Methods: Melanin content and cluster of differentiation 31 (CD31)-positive cell numbers were measured in tail skins from UVB-irradiated mice treated by intragastral or topical TXA using immunofluorescent and Fontana-Masson staining. The conditioned medium (CM) was harvested from human umbilical vein endothelial cells treated with or without 3 mM TXA and was used to treat MCs for 48 hours. mRNA and protein levels of tyrosinase and microphthalmia-associated transcription factor were measured using quantitative real-time reverse transcription polymerase chain reaction and western blotting assays. HMB45- and CD31-positive cell numbers as well as melanin content were also examined in ex vivo cultured human skin explants.

Results: The hyperpigmented phenotype were significantly mitigated in UVB-irradiated tail skin plus intragastral TXA-treated mice compared with mice treated with UVB only or with UVB plus topical TXA. CD31-positive cell numbers correlated with the anti-melanogenic activity of TXA therapy. The data from cultured cells and skin tissues showed that suppression of endothelin-1 (ET-1) in vascular endothelial cells by TXA reduced melanogenesis and MC proliferation.

Conclusion: Oral TXA outperforms topical TXA treatment in skin lightening, which contributes to suppression of ET-1 in dermal microvascular endothelial cells by TXA.