Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.
Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine.
Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia.
Jelena
J
Zlatković
Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia.
Nevena
N
Todorović
Institute of Pathology, School of Medicine, University of Belgrade, Serbia.
Nada
N
Tomanović
Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia.
Maja
M
Bošković
Poisoning Control Centre, Military Medical Academy, Belgrade, Serbia.
Snežana
S
Djordjević
Department of Physical Chemistry, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia.
Tamara
T
Lazarević-Pašti
Central Institute of Mental Health, Institute of Psychopharmacology, Mannheim, Germany.
Rick E
RE
Bernardi
Medicines and Medical Devices Agency of Serbia, Belgrade, Serbia.
Aleksandra
A
Djurdjević
Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia. Electronic address: dragana@vinca.rs.
Dragana
D
Filipović
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003024:Clozapine / Q000009:adverse effects* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005473:Fluoxetine / Q000009:adverse effects* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D013482:Superoxide Dismutase
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D016328:NF-kappa B; D005473:Fluoxetine; D009569:Nitric Oxide; D008315:Malondialdehyde; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D003024:Clozapine
Clozapine; Clozapine (PubChem CID: 2818); Fluoxetine; Fluoxetine (PubChem CID: 62857); Histopathology; Oxidative stress; Rat liver