El-Mowafy A M, Abdel-Dayem M A, Abdel-Aziz A, El-Azab M F, Said S A
Department of Biochemistry, Mansoura University, Mansoura, Egypt.
Biochim Biophys Acta. 2011 Jul-Aug;1811(7-8):460-7. doi: 10.1016/j.bbalip.2011.04.014. Epub 2011 May 5.
The omega-3 fatty acid eicosapentaenoic acid (EPA) is a superb nature's medicine, with still unfolding health benefits. Because hepatotoxicity is a prominent adverse drug reaction, we currently attempted a new approach in which EPA was challenged to both alleviate hepatotoxicity and provide synergy with anticonvulsant effects of valproate (VPA). Besides, we verified whether EPA may kinetically modulate the clearance rate of VPA. VPA (500mg/kg p.o., for 2weeks) caused rat hepatotoxicity that was manifested as notable (2- to 4-fold) rise in serum liver enzymes (GGT, ALT, and ALP), increased hepatic levels of lipid peroxides and TNF-α (3- and 7-fold) and activity of myeloperoxidase (MPO, 4-fold), lowering of serum albumin (42%), and depletion of liver reduced glutathione (GSH, 36%). Furthermore, histopathologic examination revealed hepatocellular degeneration, focal pericentral necrosis, infiltration of inflammatory cells, and steatosis. Joint treatment with EPA (300mg/kg) blunted the oxidative stress, TNF-α levels and MPO activity, while enhanced levels of serum albumin and hepatic GSH. EPA also ameliorated most of the hepatocellular anomalies evoked by VPA. Additionally, in a mouse PTZ convulsion model, EPA markedly augmented the anticonvulsant effects of VPA far beyond their single responses. On the other hand, pharmacokinetic analyses revealed that joint EPA administration had no effect on serum VPA concentrations. Collectively, results demonstrate for the first time that the ω-3 FA (EPA) markedly alleviated VPA-induced hepatotoxicity, oxidative stress, and inflammation, while enhanced its anticonvulsant effects without altering its clearance. Therapeutically, these protective and synergy profiles for EPA foster a more safe and efficacious drug combination regimen than VPA.
ω-3脂肪酸二十碳五烯酸（EPA）是一种卓越的天然药物，其对健康的益处仍在不断显现。由于肝毒性是一种突出的药物不良反应，我们目前尝试了一种新方法，即采用EPA来减轻肝毒性，并与丙戊酸（VPA）的抗惊厥作用产生协同效应。此外，我们还验证了EPA是否能在动力学上调节VPA的清除率。VPA（口服500mg/kg，持续2周）导致大鼠肝毒性，表现为血清肝酶（γ-谷氨酰转移酶、谷丙转氨酶和碱性磷酸酶）显著升高（2至4倍），肝内脂质过氧化物和肿瘤坏死因子-α水平增加（3倍和7倍）以及髓过氧化物酶（MPO）活性增强（4倍），血清白蛋白降低（42%），肝内还原型谷胱甘肽（GSH）耗竭（36%）。此外，组织病理学检查显示肝细胞变性、局灶性中央周围坏死、炎性细胞浸润和脂肪变性。与EPA（300mg/kg）联合治疗可减轻氧化应激、肿瘤坏死因子-α水平和MPO活性，同时提高血清白蛋白和肝内GSH水平。EPA还改善了VPA引起的大多数肝细胞异常。此外，在小鼠戊四氮惊厥模型中，EPA显著增强了VPA的抗惊厥作用，远远超过它们各自单独作用的效果。另一方面，药代动力学分析表明，联合给予EPA对血清VPA浓度没有影响。总体而言，结果首次表明ω-3脂肪酸（EPA）显著减轻了VPA诱导的肝毒性、氧化应激和炎症，同时增强了其抗惊厥作用，而不改变其清除率。在治疗方面，EPA的这些保护和协同作用特性促成了一种比VPA更安全有效的药物联合治疗方案。
