Yun Jun-Won, Kim MinJeong, Cho Sung-Dae, Lee Joo Young, Bae Ok-Nam, Lim Kyung-Min
Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-808, Republic of Korea.
Toxicol Lett. 2014 Aug 17;229(1):59-65. doi: 10.1016/j.toxlet.2014.06.010. Epub 2014 Jun 6.
Drug-induced hepatotoxicity is a serious adverse effect with high morbidity and mortality rates but substantial individual to individual variation is observed in its severity. Here we sought to discover factors determining the susceptibility to acetaminophen (APAP)-induced hepatotoxicity by comparing the global gene expression profile (27,342 genes) in pre-dose blood before APAP administration between susceptible and resistant animals (N=5) grouped based on the severity of hepatotoxicity. Forty-one genes were expressed differently (>1.5 fold change and p<0.05) between susceptible and resistant groups. Among them, protein kinase (cAMP-dependent) inhibitor alpha, Pkia, a member of protein kinase A (PKA) inhibitor family, was found to be most significantly and highly expressed in susceptible animals (~3.5 fold with p<0.01). To investigate the effects of PKA inhibition on APAP-induced hepatotoxicity, we pre-treated H-89, a potent and selective inhibitor of PKA, prior to APAP administration in vivo. As a result, H-89 pretreatment significantly potentiated APAP-induced hepatotoxicity as determined by the increased serum alanine transaminase. These results were further corroborated by the exacerbation of APAP-induced glutathione depletion, suppression of antioxidant enzyme system, superoxide dismutase 1 and glutathione peroxidase 1, and peroxynitrite generation in the liver following H-89 pretreatment, reflecting that PKA may be involved in the protection against, or attenuation of APAP-induced hepatotoxicity, and Pkia can be employed to screen individuals susceptible to APAP-induced hepatotoxicity.
药物性肝毒性是一种严重的不良反应，发病率和死亡率都很高，但在严重程度上个体差异很大。在这里，我们通过比较基于肝毒性严重程度分组的易感和抗性动物（N = 5）在给予对乙酰氨基酚（APAP）之前的给药前血液中的全局基因表达谱（27,342个基因），试图发现决定对APAP诱导的肝毒性易感性的因素。在易感和抗性组之间有41个基因表达不同（变化> 1.5倍且p <0.05）。其中，蛋白激酶（cAMP依赖性）抑制剂α，Pkia，蛋白激酶A（PKA）抑制剂家族的成员，被发现在易感动物中表达最显著且高度表达（约3.5倍且p <0.01）。为了研究PKA抑制对APAP诱导的肝毒性的影响，我们在体内给予APAP之前用强效和选择性PKA抑制剂H-89进行预处理。结果，H-89预处理显著增强了APAP诱导的肝毒性，这由血清丙氨酸转氨酶升高来确定。H-89预处理后肝脏中APAP诱导的谷胱甘肽耗竭加剧、抗氧化酶系统超氧化物歧化酶1和谷胱甘肽过氧化物酶1的抑制以及过氧亚硝酸盐的产生进一步证实了这些结果，这表明PKA可能参与了对APAP诱导的肝毒性的保护或减轻作用，并且Pkia可用于筛选对APAP诱导的肝毒性易感的个体。
