Adv Pharm Bull. 2016;6(4): 521-530.
doi: 10.15171/apb.2016.066
PMID: 28101459
PMCID: PMC5241410
Scopus ID: 85011382287
  Abstract View: 2400
  PDF Download: 1403

Research Article

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction

Elham Ahmadian 1,2,3,4, Hossein Babaei 2,3, Alireza Mohajjel Nayebi 3, Aziz Eftekhari 3,4, Mohammad Ali Eghbal 2,3*

1 Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
4 Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
*Corresponding Author: Email: m.a.eghbal@hotmail.com


Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
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Submitted: 04 May 2016
Revision: 19 Oct 2016
Accepted: 24 Oct 2016
ePublished: 22 Dec 2016
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