Le, YuanChen, LimingZhang, YueBu, PengliDai, GuoliCheng, Xingguo2024-07-112024-07-112018Le Y, Chen L, Zhang Y, Bu P, Dai G, Cheng X. Epalrestat Stimulated Oxidative Stress, Inflammation, and Fibrogenesis in Mouse Liver. Toxicol Sci. 2018;163(2):397-408. doi:10.1093/toxsci/kfx038https://hdl.handle.net/1805/42132Epalrestat (EPS), an aldose reductase inhibitor, is widely prescribed to manage diabetic neuropathy. It is generally believed that EPS is beneficial to diabetic patients because it can protect endothelial cells, Schwann cells, or other neural cells from oxidative stress. However, several clinical studies revealed that EPS therapy led to liver dysfunction, which limited its clinical applications. Currently, the underlying mechanism by which EPS causes liver dysfunction is unknown. This study aimed to investigate the mechanism responsible for EPS-induced liver injury. In mouse liver, EPS 1) increased oxidative stress, indicated by increased expression of manganese superoxide dismutase, Ho-1, and Nqo1, 2) induced inflammation, indicated by infiltration of inflammatory cells, and induced expression of tumor necrosis factor-alpha, CD11b, and CD11c, as well as 3) predisposed to induce fibrosis, evidenced by increased mRNA and protein expression of early profibrotic biomarker genes procollagen I and alpha-smooth muscle actin, and by increased collagen deposition. In cultured mouse and human hepatoma cells, EPS treatment induced oxidative stress, decreased cell viability, and triggered apoptosis evidenced by increased Caspase-3 cleavage/activation. In addition, EPS increased mRNA and protein expression of cytoglobin in mouse liver, indicating that EPS activated hepatic stellate cells (HSCs). Furthermore, EPS treatment in cultured human HSCs increased cell viability. In summary, EPS administration induced oxidative stress and inflammation in mouse liver, and stimulated liver fibrogenesis. Therefore, cautions should be exercised during EPS therapy.en-USPublisher PolicyEpalrestatInflammationLiver fibrosisOxidative stressArticle