Tabriz University of Medical Sciences About    Newsletter    Contact Us    Create Account    Log in  
Advanced Pharmaceutical Bulletin
ISSN: 2228-5881      eISSN: 2251-7308  
Services
Export citation
EndNote
Reference Manager
BibTeX
Medlars
Refworks
Mendeley

Cite by
Google Scholar



Article History
Submitted: 04 May 2016
Revised: 19 Oct 2016
Accepted: 24 Oct 2016
First published online: 22 Dec 2016

Article Access Statistics
Abstract Page Views: 176
PDF Downloads: 106
Full Text Views: 0

Adv Pharm Bull. 2016;6(4):521-530 doi: 10.15171/apb.2016.066

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



Research Article

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.



Abstract
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.





Comments
First name  
Last name  
Email address  
Comments  
Security code



This Article
PDF

Google Scholar
Articles by Ahmadian E
Articles by Babaei H
Articles by Mohajjel Nayebi A
Articles by Eftekhari A
Articles by Eghbal MA

PubMed
Articles by Ahmadian E
Articles by Babaei H
Articles by Mohajjel Nayebi A
Articles by Eftekhari A
Articles by Eghbal MA



Share this article!

Press Manuscript Online. Powered by MAADRAYAN