Nicotinic Acid against Acetaminophen-Induced Hepatotoxicity via Sirt1/Nrf2 Antioxidative Pathway in Mice

• Published in: Journal of Nutritional Science and Vitaminology 2021/06/30, Vol.67(3), pp.145-152
• Main Authors: HU, Da, ZHANG, Li, JIANG, Rong, LIAO, Cuiting, XU, Juanjuan, JIANG, Shifang, YANG, Yongqiang, LIN, Ling, HUANG, Jiayi, SHEN, Yi, TANG, Li, LI, Longjiang
• Format: Article
• Language: English
• Subjects: acetaminophen; nicotinic acid; Nrf2; oxidative stress; Sirt1
• ISSN: 0301-4800; 1881-7742
• DOI: 10.3177/jnsv.67.145

Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose causes hepatotoxicity, even liver failure, and oxidative stress plays pivotal role in its pathogenesis. Nicotinic acid (NA) is one form of vitamin B3, which has been used to treat a series of diseases in clinic for decades. To date, several studies have evidenced that NA has anti-oxidative property. Therefore, NA may have the hepatoprotective potential against APAP-induced toxicity. Here, our aim was to investigate the beneficial effect of NA against hepatotoxicity induced by APAP and its mechanism in vivo. BALB/c mice were intraperitoneally injected with NA (100 mg/kg) 3 times at 24, 12 and 1 h before APAP (600 mg/kg or 400 mg/kg) challenge. The results showed that pretreatment of NA markedly improved the survival rate, alleviated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and mitigated the histopathological injuries compared to APAP-exposed mice. Furthermore, NA significantly elevated the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) content, while reduced malondialdehyde (MDA) level. Finally, the signaling pathway was probed. The western blot revealed that NA up-regulated Sirtuin1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H quinone dehydrogenase-1 (NQO-1) expression and down-regulated Kelch-like ECH-associated protein 1 (Keap1) level in liver followed APAP exposure, implying Sirt1/Nrf2 axis exerted an essential role in the protective mechanism of NA on APAP toxicity. In brief, pretreatment of NA effectively protects liver against hepatotoxicity due to overdose of APAP through an antioxidant dependent manner modulated by Sirt1/Nrf2 signaling pathway.