Fluoxetine affects antioxidant system and promotes apoptotic signaling in Wistar rat liver
Abstract
Selective serotonin reuptake inhibitors (SSRI) are a treatment of choice for stress related disorders including clinical depression and a range of anxiety-related disorders. In the experimental animals, chronic stress paradigms are considered as a model of depression, and in that context are used for examining the effects of different drug treatments. The present research was designed to investigate the effect of SSRI fluoxetine on antioxidant status and apoptotic signaling in Wistar rat liver, which is a central organ for activation and detoxification of many xenobiotics and reactive oxygen species. We also investigated whether chronic fluoxetine treatment exhibits the same effects in the liver of control animals vs. animals stressed by chronic psychosocial isolation. Our results revealed that fluoxetine downregulated the activity of superoxide dismutases and upregulated the activity of glutathione peroxidase in both rat groups, while elevating glutathione reductase activity and total antioxidant status only in stressed animals. These results suggested that fluoxetine interfered with stress-induced pathways of oxidative defense in the liver. In addition, in both experimental groups, fluoxetine induced several hallmarks of apoptosis in the liver, including a decrease in Bcl-2 expression and increased DNA fragmentation. However, apoptotic alterations were more pronounced in stressed animals, suggesting that stress related oxidative damage could have primed apoptotic effects of fluoxetine.
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After 21 days of fluoxetine treatment, male rat liver displays altered antioxidant status and increased apoptotic signalling.
“Djordjevic et al. (2011) showed altered antioxidant status and increased apoptotic signalling in male rat liver after 21 days of fluoxetine treatment.”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [25]
Fluoxetine alters several markers of apoptosis in the liver, including decreased Bcl-2 expression and increased DNA fragmentation.
“fluoxetine altered several markers of apoptosis in the liver, including decreased Bcl-2 expression and increased DNA fragmentation [25].”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [25]
In control and stressed animals, fluoxetine treatment decreases SOD activity and increases GPx activity.
“Control animals and stressed animals displayed decreased activity of SOD and increased activity of GPx.”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [25]
These effects seemed to be associated with liver toxicity induced by high-dose fluoxetine treatment in rats.
“These effects seemed to be associated with liver toxicity induced by high-dose fluoxetine treatment in rats.”
From Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder (2012) · cites this paper as [25]
Cites
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
LAEMMLI, U. K. (1970) · Nature · doi:10.1038/227680a0 · Cited by 249,961 · see citing works
Markwell, M. A. K., Haas, S. M., BIEBER, L. L., & Tolbert, N. E. (1978) · Analytical Biochemistry · doi:10.1016/0003-2697(78)90586-9 · Cited by 6,460 · see citing works
Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked
Yang, J., Liu, X., Bhalla, K. N., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., & Wang, X. (1997) · Science · doi:10.1126/science.275.5303.1129 · Cited by 4,913 · see citing works
BCL-2 family members and the mitochondria in apoptosisPreprint
Gross, A., McDonnell, J. M., & Korsmeyer, S. J. (1999) · Genes & Development · doi:10.1101/gad.13.15.1899 · Cited by 3,623 · see citing works
Kohen, R., & Nyska, A. (2002) · Toxicologic Pathology · doi:10.1080/01926230290166724 · Cited by 2,178 · see citing works
Willner, P. (1997) · Psychopharmacology · doi:10.1007/s002130050456 · Cited by 1,832 · see citing works
Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function.
Fialkow, L., Wang, Y.-C., & Downey, G. (2007) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2006.09.030 · Cited by 722 · see citing works
Bilici, M., Efe, H., Köroğlu, M. A., Uydu, H. A., Bekaroğlu, M., & Değer, O. (2001) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00199-3 · Cited by 718 · see citing works
Wong, D. T., Bymaster, F. P., & Engleman, E. A. (1995) · Life Sciences · doi:10.1016/0024-3205(95)00209-o · Cited by 647 · see citing works
Crewe, H. K., Lennard, M., Tucker, G., Woods, F. R., & Haddock, R. E. (1992) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1992.tb04134.x · Cited by 468 · see citing works
Khanzode, S. D., Dakhale, G. N., Khanzode, S. S., Saoji, A., & Palasodkar, R. (2003) · Redox Report · doi:10.1179/135100003225003393 · Cited by 458 · see citing works
Indicators of immune activation in major depression
Sluzewska, A., RYBAKOWSKI, J. K., Bosmans, E., Sobieska, M., Berghmans, R., Maes, M. H. J., & Wiktorowicz, K. (1996) · Psychiatry Research · doi:10.1016/s0165-1781(96)02783-7 · Cited by 384 · see citing works
Madrigal, J. L. M. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00208-6 · Cited by 381 · see citing works
Murphy, K. M., Ranganathan, V., Farnsworth, M. L., Kavallaris, M., & Lock, R. B. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400597 · Cited by 356 · see citing works
Clinical Pharmacokinetics of Fluoxetine
Altamura, A. C., Moro, A. R., & Percudani, M. (1994) · Clinical Pharmacokinetics · doi:10.2165/00003088-199426030-00004 · Cited by 336 · see citing works
The immune system, depression and the action of antidepressants
Leonard, B. E. (2001) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(01)00155-5 · Cited by 333 · see citing works
Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.
Detke, M. J., Johnson, J. E., & Lucki, I. (1997) · Experimental and Clinical Psychopharmacology · doi:10.1037/1064-1297.5.2.107 · Cited by 318 · see citing works
Almeida, O. F. X., Conde, G., Crochemore, C., DEMENEIX, B. A., Fischer, D., Hassan, A. H., Meyer, M., Holsboer, F., & Michaelidis, T. M. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.5.779 · Cited by 278 · see citing works
Lucassen, P. J., Fuchs, E., & Czéh, B. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.12.014 · Cited by 201 · see citing works
Chronic cold exposure affects the antioxidant defense system in various rat tissues
Kaushik, S., & Kaur, J. (2003) · Clinica Chimica Acta · doi:10.1016/s0009-8981(03)00171-2 · Cited by 194 · see citing works
Serafeim, A., Holder, M. J., Grafton, G., Chamba, A., Drayson, M. T., Luong, Q. T., Bunce, C. M., Gregory, C. D., Barnes, N. M., & Gordon, J. (2003) · Blood · doi:10.1182/blood-2002-07-2044 · Cited by 174 · see citing works
Zimmermann, R., Flohé, L., Weser, U., & Hartmann, H. (1973) · FEBS Letters · doi:10.1016/0014-5793(73)80539-3 · Cited by 158 · see citing works
Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats
Zafir, A., & Banu, N. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.05.062 · Cited by 156 · see citing works
DNA fragmentation in rat brain after intraperitoneal administration of kainate
Filipkowski, R. K., Hetman, M., Kamińska, B., et al. (1994) · Neuroreport · doi:10.1097/00001756-199407000-00032 · Cited by 132 · see citing works
Gałecki, P., Szemraj, J., Bieńkiewicz, M., Zboralski, K., & Gałecka, E. (2009) · Human Psychopharmacology: Clinical and Experimental · doi:10.1002/hup.1014 · Cited by 124 · see citing works
Herrera, B. M., Fernández, M., Alvarez, A. M., Roncero, C., Benito, M., Gil, J., & Fabregat, I. (2001) · Hepatology · doi:10.1053/jhep.2001.27447 · Cited by 118 · see citing works
Induction of oxidative stress by restraint stress and corticosterone treatments in rats.
Zafir, A., & Banu, N. (2009) · PubMed · Cited by 100 · see citing works
Effect of fluoxetine on rat liver mitochondria
Souza, M. E. J., Polizello, A. C. M., Uyemura, S. A., Castro-Silva, O., & Curti, C. (1994) · Biochemical Pharmacology · doi:10.1016/0006-2952(94)90283-6 · Cited by 95 · cited 1× · see citing works
“Fluoxetine and norfluoxetine were found to exert potentially toxic multiple effects on energy metabolism in rat liver mitochondria (Souza et al., 1994).”
BackgroundNaphthalene-Induced Oxidative Stress and DNA Damage in Cultured Macrophage J774A.1 Cells
Bagchi, M., Bagchi, D., Balmoori, J., Ye, X., & STOHS, S. J. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00063-x · Cited by 84 · see citing works
Djordjevic, J., Djordjevic, A. D., Adzic, M., et al. (2010) · Physiological Research · doi:10.33549/physiolres.931862 · Cited by 81 · see citing works
Self-citationAcute Hepatitis Due to Fluoxetine Therapy
Cai, Q., Benson, M. A., Talbot, T. J., Devadas, G., Swanson, H. J., Olson, J. L., & Kirchner, J. P. (1999) · Mayo Clinic Proceedings · doi:10.4065/74.7.692 · Cited by 55 · see citing works
Prabhakar, A. H., Patel, V. B., & Giridhar, R. (1999) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/s0731-7085(98)00255-6 · Cited by 52 · see citing works
Zhai, F., Zhang, X., & Wang, H. (2009) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2009.05168.x · Cited by 44 · see citing works
Chronic hepatitis related to use of fluoxetine.
Johnston, D. E., & Wheeler, D. E. (1997) · PubMed · Cited by 38 · see citing works
Thompson, D. C., Perera, K., & London, R. E. (2000) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(99)00162-3 · Cited by 38 · see citing works
Antioxidant activity of fluoxetine: Studies in mice melanoma model
Kirkova, M., Tzvetanova, E., Vircheva, S., Zamfirova, R., Grygier, B., & Kubera, M. (2010) · Cell Biochemistry and Function · doi:10.1002/cbf.1682 · Cited by 37 · see citing works
Overview on the mechanisms of drug-induced liver cell death
Grattagliano, I., Portincasa, P., Palmieri, V. O., & Palasciano, G. (2002) · Annals of Hepatology · doi:10.1016/s1665-2681(19)32160-x · Cited by 36 · see citing works
Hepatitis secondary to fluoxetine treatment
Friedenberg, F. K., & Rothstein, K. D. (1996) · American Journal of Psychiatry · doi:10.1176/ajp.153.4.580a · Cited by 30 · see citing works
Platelet Serotonin Acts as a Locally Releasable Antioxidant
Huether, G., & Schuff‐Werner, P. (1996) · Advances in experimental medicine and biology · doi:10.1007/978-1-4613-0381-7_47 · Cited by 21 · see citing works
Elaković, I., Vasiljević, Đ., Adžić, M., Djordjevic, A. D., Djordjevic, J., Radojcic, M. B., & Matić, G. M. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.01.015 · Cited by 9 · see citing works
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Behr, G. A., Moreira, J. C. F., & Frey, B. N. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/609421 · Cited by 205 · see citing works
Lindqvist, D., Wolkowitz, O. M., Picard, M., Ohlsson, L., Bersani, F. S., Fernström, J., Westrin, Å., Hough, C. M., Lin, J., Reus, V. I., et al. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-017-0001-9 · Cited by 188 · see citing works
- Authors
- Djordjevic, J., Djordjevic, A., Adzic, M., Elaković, I., Matić, G., & Radojcic, M. B.
- Affiliations
- Vinča Institute of Nuclear Sciences (RS)
- University of Belgrade (RS)
- Corresponding author
- Djordjevic, Jelena
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 659
- Issue
- 1
- Pages
- 61-66
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W1992411493
- Semantic Scholar
- 5c4a33b0e09e28b8904f12605b0c3f9c81158098
- Cited by
- 78
- References
- 40
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 14 · 2020: 10 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 4 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 4
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Digital Repository of Archived Publications (University of Belgrade, Institute for Biological Research Sinisa Stankovic) (submittedVersion)
- VinaR (Institute of Nuclear Sciences "Vinča") (submittedVersion)
- Funders
- Science and Engineering Research Board
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- fluoxetine, selective serotonin reuptake inhibitors, chronic stress, depression model, liver, oxidative stress, antioxidant status, apoptosis, Bcl-2, DNA fragmentation, superoxide dismutase, glutathione peroxidase, glutathione reductase, total antioxidant capacity, reactive oxygen species
- MeSH terms
- Animals, Antioxidants, Fluoxetine, Gene Expression Regulation, Liver, Male, Signal Transduction, Rats, Wistar, Apoptosis, Selective Serotonin Reuptake Inhibitors, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Rats, DNA Fragmentation
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