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