Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
Department of Anatomy and Cell Biology, Medical School, Kangwon National University, Chunchon, 24341, Republic of Korea.
Biochimie. 2019 Mar;158:53-61. doi: 10.1016/j.biochi.2018.12.009. Epub 2018 Dec 18.
Cocaine, an addictive drug, is known to induce hepatotoxicity via oxidative damage and proapoptosis. Since p53, a tumor suppressor gene, plays a major role in inducing oxidative stress and apoptosis, we examined the role of p53 inhibition against cocaine-induced hepatotoxicity. Cocaine treatment significantly increased oxidative parameters (i.e., reactive oxygen species, 4-hydroxylnonenal, and protein carbonyl) in the liver of wild type (WT) mice. We found that the pharmacological (i.e. pifithrin-α) and genetic (i.e. p53 knockout) inhibition of p53 significantly attenuates cocaine-induced hepatotoxicity. Cocaine treatment increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of mice, signifying hepatic damage. Consistently, these increases were attenuated by inhibition of p53, implying protection against cocaine-induced hepatic damage. In addition, cocaine treatment significantly increased PKCδ, cleaved PKCδ and p53 levels in the liver of WT mice. These increases were followed by the interaction between p53 and PKCδ, and pro-apoptotic consequences (i.e., cytosolic release of cytochrome c, activation of caspase-3, increase in Bax level and decreases in Bcl-2 and Bcl-xL levels). These changes were attenuated by p53 depletion, reflecting that the critical role of PKCδ in p53-mediated apoptotic potentials. Combined, our results suggest that the inhibition of p53 is important for protection against oxidative burdens, pro-apoptotic events, and hepatic degeneration induced by cocaine.
可卡因是一种成瘾性药物，已知会通过氧化损伤和促进细胞凋亡导致肝毒性。由于肿瘤抑制基因 p53 在诱导氧化应激和细胞凋亡中起着重要作用，我们研究了抑制 p53 对可卡因诱导的肝毒性的作用。可卡因处理显著增加了野生型（WT）小鼠肝脏中的氧化参数（即活性氧、4-羟基壬烯醛和蛋白质羰基）。我们发现，p53 的药理学（即 pifithrin-α）和遗传学（即 p53 敲除）抑制显著减轻了可卡因诱导的肝毒性。可卡因处理增加了小鼠血清中的丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平，表明肝损伤。一致地，这些增加被 p53 抑制所减弱，暗示对可卡因诱导的肝损伤的保护作用。此外，可卡因处理显著增加了 WT 小鼠肝脏中 PKCδ、裂解的 PKCδ 和 p53 的水平。这些增加伴随着 p53 和 PKCδ 之间的相互作用，以及促凋亡后果（即细胞色素 c 的细胞质释放、caspase-3 的激活、Bax 水平的增加和 Bcl-2 和 Bcl-xL 水平的降低）。这些变化被 p53 耗竭减弱，反映了 PKCδ 在 p53 介导的凋亡潜能中的关键作用。综上所述，我们的结果表明，抑制 p53 对于防止可卡因引起的氧化应激、促凋亡事件和肝变性至关重要。
