Investigation on inhibitory effect of folic acid on methotrexate-induced epithelial-mesenchymal transition focusing on dihydrofolate reductase

• Published in: Drug metabolism and pharmacokinetics 2019-12, Vol.34 (6), p.396-399
• Main Authors: Kawami, Masashi, Honda, Natsuko, Hara, Takuya, Yumoto, Ryoko, Takano, Mikihisa
• Format: Article
• Language: English
• Subjects: Alveolar epithelial cells; Dihydrofolate reductase; Epithelial-mesenchymal transition; Folate; Methotrexate
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2019.08.003

Use of methotrexate (MTX) can induce serious adverse lung reactions, such as pulmonary fibrosis. Recently, we demonstrated that the epithelial-mesenchymal transition (EMT), which triggers pulmonary fibrosis, was induced by MTX, and folic acid (FA) suppressed MTX-induced EMT in A549 cells. In this study, the role of dihydrofolate reductase (DHFR), a target of MTX, in FA-mediated inhibition of MTX-induced EMT was evaluated. The inhibitory effects of FA and tetrahydrofolate (THF), a metabolite of FA produced by DHFR, on MTX-induced increases in mRNA expression of α-SMA, an EMT marker, were compared. The IC50 values of FA and THF for DHFR were 103.3 and 19.4 μM, respectively. In contrast, DHFR knockdown did not alter the mRNA expression of α-SMA. Notably, the inhibitory effect of FA, but not THF, on MTX-induced EMT was blunted in DHFR knockdown cells. These results suggested that DHFR may not directly contribute to MTX-induced EMT, but may contribute to suppression of MTX-induced EMT via production of THF in A549 cells. [Display omitted]