Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction
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2021
Authors
Platanić Arizanović, LenaNikolić-Kokić, Aleksandra

Brkljačić, Jelena
Tatalović, Nikola

Miler, Marko
Oreščanin-Dušić, Zorana

Vidonja Uzelac, Teodora
Nikolić, Milan

Milošević, Verica
Blagojević, Duško P.

Spasić, Snežana

Miljević, Čedo

Article (Published version)

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Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-modera...te hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.
Keywords:
Animals / Antioxidants / antioxidative enzymes / Antipsychotic Agents / Clozapine / Imidazoles / Indoles / liver / Liver / Liver Diseases / Male / Piperazines / Rats / Rats, Wistar / sertindole / Thiazoles / ziprasidoneSource:
Journal of Toxicology and Environmental Health. Part A, 2021, 84, 4, 173-182Publisher:
- Taylor and Francis
Funding / projects:
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-200007)
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200178 (University of Belgrade, Faculty of Biology) (RS-200178)
DOI: 10.1080/15287394.2020.1844827
ISSN: 1528-7394
WoS: 000592044000001
Scopus: 2-s2.0-85096601923
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Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Platanić Arizanović, Lena AU - Nikolić-Kokić, Aleksandra AU - Brkljačić, Jelena AU - Tatalović, Nikola AU - Miler, Marko AU - Oreščanin-Dušić, Zorana AU - Vidonja Uzelac, Teodora AU - Nikolić, Milan AU - Milošević, Verica AU - Blagojević, Duško P. AU - Spasić, Snežana AU - Miljević, Čedo PY - 2021 UR - http://www.ncbi.nlm.nih.gov/pubmed/33234086 UR - http://cherry.chem.bg.ac.rs/handle/123456789/4778 AB - Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment. PB - Taylor and Francis T2 - Journal of Toxicology and Environmental Health. Part A T2 - Journal of Toxicology and Environmental Health. Part AJ Toxicol Environ Health A T1 - Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction VL - 84 IS - 4 SP - 173 EP - 182 DO - 10.1080/15287394.2020.1844827 ER -
@article{ author = "Platanić Arizanović, Lena and Nikolić-Kokić, Aleksandra and Brkljačić, Jelena and Tatalović, Nikola and Miler, Marko and Oreščanin-Dušić, Zorana and Vidonja Uzelac, Teodora and Nikolić, Milan and Milošević, Verica and Blagojević, Duško P. and Spasić, Snežana and Miljević, Čedo", year = "2021", abstract = "Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.", publisher = "Taylor and Francis", journal = "Journal of Toxicology and Environmental Health. Part A, Journal of Toxicology and Environmental Health. Part AJ Toxicol Environ Health A", title = "Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction", volume = "84", number = "4", pages = "173-182", doi = "10.1080/15287394.2020.1844827" }
Platanić Arizanović, L., Nikolić-Kokić, A., Brkljačić, J., Tatalović, N., Miler, M., Oreščanin-Dušić, Z., Vidonja Uzelac, T., Nikolić, M., Milošević, V., Blagojević, D. P., Spasić, S.,& Miljević, Č.. (2021). Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction. in Journal of Toxicology and Environmental Health. Part A Taylor and Francis., 84(4), 173-182. https://doi.org/10.1080/15287394.2020.1844827
Platanić Arizanović L, Nikolić-Kokić A, Brkljačić J, Tatalović N, Miler M, Oreščanin-Dušić Z, Vidonja Uzelac T, Nikolić M, Milošević V, Blagojević DP, Spasić S, Miljević Č. Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction. in Journal of Toxicology and Environmental Health. Part A. 2021;84(4):173-182. doi:10.1080/15287394.2020.1844827 .
Platanić Arizanović, Lena, Nikolić-Kokić, Aleksandra, Brkljačić, Jelena, Tatalović, Nikola, Miler, Marko, Oreščanin-Dušić, Zorana, Vidonja Uzelac, Teodora, Nikolić, Milan, Milošević, Verica, Blagojević, Duško P., Spasić, Snežana, Miljević, Čedo, "Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction" in Journal of Toxicology and Environmental Health. Part A, 84, no. 4 (2021):173-182, https://doi.org/10.1080/15287394.2020.1844827 . .