Ahmadian Elham, Babaei Hossein, Mohajjel Nayebi Alireza, Eftekhari Aziz, Eghbal Mohammad Ali
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Adv Pharm Bull. 2016 Dec;6(4):521-530. doi: 10.15171/apb.2016.066. Epub 2016 Dec 22.
Depression is a public disorder worldwide. Despite the widespread use of venlafaxine in the treatment of depression, it has been associated with the incidence of toxicities. Hence, the goal of the current investigation was to evaluate the mechanisms of venlafaxine-induced cell death in the model of the freshly isolated rat hepatocytes. Collagenase-perfused rat hepatocytes were treated with venlafaxine and other agents. Cell damage, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential decline, lysosomal damage, glutathione (GSH) level were analyzed. Moreover, rat liver mitochondria were isolated through differential centrifugation to assess respiratory chain functionality. Our results demonstrated that venlafaxine could induce ROS formation followed by lipid peroxidation, cellular GSH content depletion, elevated GSSG level, loss of lysosmal membrane integrity, MMP collapse and finally cell death in a concentration-dependent manner. N-acetyl cysteine, taurine and quercetine significantly decreased the aforementioned venlafaxine-induced cellular events. Also, radical scavenger (butylatedhydroxytoluene and α-tocopherol), CYP2E1 inhibitor (4-methylpyrazole), lysosomotropic agents (methylamine and chloroquine), ATP generators (L-gluthamine and fructose) and mitochondrial pore sealing agents (trifluoperazine and L-carnitine) considerably reduced cytotoxicity, ROS generation and lysosomal leakage following venlafaxine treatment. Mitochondrion dysfunction was concomitant with the blockade of the electron transfer complexes II and IV of the mitochondrial respiratory system. Therefore, our data indicate that venlafaxine induces oxidative stress towards hepatocytes and our findings provide evidence to propose that mitochondria and lysosomes are of the primary targets in venlafaxine-mediated cell damage.
抑郁症是一种全球性的公共疾病。尽管文拉法辛在抑郁症治疗中被广泛使用，但它与毒性的发生有关。因此，本研究的目的是评估文拉法辛在新鲜分离的大鼠肝细胞模型中诱导细胞死亡的机制。用胶原酶灌注的大鼠肝细胞用文拉法辛和其他药物处理。分析细胞损伤、活性氧（ROS）形成、脂质过氧化、线粒体膜电位下降、溶酶体损伤、谷胱甘肽（GSH）水平。此外，通过差速离心分离大鼠肝脏线粒体以评估呼吸链功能。我们的结果表明，文拉法辛可诱导ROS形成，随后发生脂质过氧化、细胞GSH含量耗竭、GSSG水平升高、溶酶体膜完整性丧失、MMP崩溃，最终以浓度依赖性方式导致细胞死亡。N-乙酰半胱氨酸、牛磺酸和槲皮素显著减少了上述文拉法辛诱导的细胞事件。此外，自由基清除剂（丁基羟基甲苯和α-生育酚）、CYP2E1抑制剂（4-甲基吡唑）、溶酶体促渗剂（甲胺和氯喹）、ATP生成剂（L-谷氨酰胺和果糖）和线粒体孔封闭剂（三氟拉嗪和L-肉碱）在文拉法辛处理后显著降低了细胞毒性、ROS生成和溶酶体渗漏。线粒体功能障碍与线粒体呼吸系统电子传递复合物II和IV的阻断同时发生。因此，我们的数据表明文拉法辛对肝细胞诱导氧化应激，我们的研究结果提供了证据，表明线粒体和溶酶体是文拉法辛介导的细胞损伤的主要靶点。
