Shi Chenxi, Hao Beili, Yang Yang, Muhammad Ishfaq, Zhang Yuanyuan, Chang Yicong, Li Ying, Li Changwen, Li Rui, Liu Fangping
College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
Front Pharmacol. 2019 Sep 20;10:1092. doi: 10.3389/fphar.2019.01092. eCollection 2019.
Acetaminophen (APAP) is an analgesic-antipyretic drug and widely used in clinics. Its overdose may cause serious liver damage. Here, we examined the mechanistic role of c-Jun N-terminal kinase (JNK) signaling pathway in liver injury induced by different doses of APAP. Male mice were treated with APAP (150 and 175 mg·kg), and meanwhile JNK inhibitor SP600125 was used to interfere APAP-induced liver damage. The results showed that JNK signaling pathway was activated by APAP in a dose-dependent manner. C-Jun N-terminal kinase inhibitor decreased JNK and c-Jun activation significantly ( < 0.01) at 175 mg·kg APAP dose, and phosphorylation levels of upstream proteins of JNK were also decreased markedly ( < 0.05). In addition, serum aminotransferases activities and hepatic oxidative stress increased in a dose-dependent manner with APAP treatment, but the levels of aminotransferases and oxidative stress decreased in mice treated with JNK inhibitor, which implied that JNK inhibition ameliorated APAP-induced liver damage. It was observed that apoptosis was increased in APAP-induced liver injury, and SP600125 can attenuate apoptosis through the inhibition of JNK phosphorylation. Meanwhile, glutathione S-transferases A1 (GSTA1) content in serum was enhanced, while GSTA1 content and expression in liver reduced significantly with administration of APAP (150 and 175 mg·kg). After inhibiting JNK, GSTA1 content in serum decreased significantly ( < 0.01); meanwhile, GSTA1 content and expression in liver enhanced. These findings suggested that JNK signaling pathway mediated APAP-induced hepatic injury, which was accompanied by varying GSTA1 content and expression in liver and serum.
对乙酰氨基酚（APAP）是一种解热镇痛药，在临床上广泛使用。其过量服用可能会导致严重的肝损伤。在此，我们研究了c-Jun氨基末端激酶（JNK）信号通路在不同剂量APAP诱导的肝损伤中的作用机制。对雄性小鼠给予APAP（150和175mg·kg）处理，同时使用JNK抑制剂SP600125干预APAP诱导的肝损伤。结果显示，APAP以剂量依赖性方式激活JNK信号通路。在175mg·kg APAP剂量下，JNK抑制剂显著降低了JNK和c-Jun的激活水平（<0.01），JNK上游蛋白的磷酸化水平也明显降低（<0.05）。此外，随着APAP处理，血清氨基转移酶活性和肝脏氧化应激呈剂量依赖性增加，但在使用JNK抑制剂处理的小鼠中，氨基转移酶水平和氧化应激降低，这表明抑制JNK可改善APAP诱导的肝损伤。观察到APAP诱导的肝损伤中细胞凋亡增加，SP600125可通过抑制JNK磷酸化减轻细胞凋亡。同时，血清中谷胱甘肽S-转移酶A1（GSTA1）含量增加，而给予APAP（150和175mg·kg）后肝脏中GSTA1含量和表达显著降低。抑制JNK后，血清中GSTA1含量显著降低（<0.01）；同时，肝脏中GSTA1含量和表达增强。这些发现表明，JNK信号通路介导了APAP诱导的肝损伤，同时肝脏和血清中GSTA1的含量和表达也发生了变化。
