Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos
Ano de defesa: | 2018 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , |
Tipo de documento: | Dissertação |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências Naturais e Exatas |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica
|
Departamento: |
Bioquímica
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/18788 |
Resumo: | Cisplatin is a widely used chemotherapeutic to treat several types of tumors on both adult and pediatric subjects. Although cisplatin is widely used, its use is associated with serious toxic effects, including nephrotoxicity and hepatotoxicity. Thus, the present study investigated the effects caused by cisplatin acute administration on newborn Wistar rats and the differences in the drug toxicity compared to adult rats. The study was carried out using male and female Wistar rats 10 and 60 day-old (CEUA nº 2699300315). Rats received cisplatin at doses of 5 and 10 mg/kg, by the intraperitoneal (ip.) route, whereas the control group received saline (0.9%, ip.). After 24 h of cisplatin/saline administration, the animals were killed and samples of blood, liver, and kidneys were collected for ex vivo analyses. Markers of renal (urea) and hepatic damage (alanine aminotransferase and aspartate aminotransferase activities) were determined in the serum samples. Parameters of oxidative stress (levels of reactive oxygen species, lipid peroxidation, carbonyl protein, non-protein thiols (NPSH)); activities of antioxidant enzymes (superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione- S-transferase and glutathione reductase) and activities of sulfhydryl enzymes (δ-aminolevulinate dehydratase (δ-ALA-D) and Na +, K + - ATPase) were determined in samples of liver and kidney of rats. The levels of proteins related to oxidative stress and apoptosis were also determined in samples of liver and kidney of rats at both ages. The cisplatin acute administration caused hepatorenal toxicity in both neonatal and adult rats. However, the pattern and the severity of the damages were different among the ages and tissues. Newborn rats presented greater oxidative metabolic damage when compared to adult rats, characterized by an increase in reactive species and carbonyl protein levels, lower NPSH content, and greater inhibition of δ-ALA-D and CAT activities. In addition, a faster molecular response was found in the protein levels involved with apoptosis and response to oxidative stress. In conclusion, the data from this study show that the pattern of cisplatin toxic effects was different among the ages and tissues of rats. The present study also revealed that newborn rats are more sensitive to treatment with cisplatin for at least the first 24 h and further showed that liver damage, at least in the beginning, was greater than renal damage in adult rats. Thus, the present study demonstrated that there are differences in the body response to acute exposure of cisplatin among adult and newborn rats, reinforcing the need for further studies on children response to chemotherapy and possible effective strategies to minimize the damage caused by cisplatin. |
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2019-11-04T19:04:40Z2019-11-04T19:04:40Z2018-07-20http://repositorio.ufsm.br/handle/1/18788Cisplatin is a widely used chemotherapeutic to treat several types of tumors on both adult and pediatric subjects. Although cisplatin is widely used, its use is associated with serious toxic effects, including nephrotoxicity and hepatotoxicity. Thus, the present study investigated the effects caused by cisplatin acute administration on newborn Wistar rats and the differences in the drug toxicity compared to adult rats. The study was carried out using male and female Wistar rats 10 and 60 day-old (CEUA nº 2699300315). Rats received cisplatin at doses of 5 and 10 mg/kg, by the intraperitoneal (ip.) route, whereas the control group received saline (0.9%, ip.). After 24 h of cisplatin/saline administration, the animals were killed and samples of blood, liver, and kidneys were collected for ex vivo analyses. Markers of renal (urea) and hepatic damage (alanine aminotransferase and aspartate aminotransferase activities) were determined in the serum samples. Parameters of oxidative stress (levels of reactive oxygen species, lipid peroxidation, carbonyl protein, non-protein thiols (NPSH)); activities of antioxidant enzymes (superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione- S-transferase and glutathione reductase) and activities of sulfhydryl enzymes (δ-aminolevulinate dehydratase (δ-ALA-D) and Na +, K + - ATPase) were determined in samples of liver and kidney of rats. The levels of proteins related to oxidative stress and apoptosis were also determined in samples of liver and kidney of rats at both ages. The cisplatin acute administration caused hepatorenal toxicity in both neonatal and adult rats. However, the pattern and the severity of the damages were different among the ages and tissues. Newborn rats presented greater oxidative metabolic damage when compared to adult rats, characterized by an increase in reactive species and carbonyl protein levels, lower NPSH content, and greater inhibition of δ-ALA-D and CAT activities. In addition, a faster molecular response was found in the protein levels involved with apoptosis and response to oxidative stress. In conclusion, the data from this study show that the pattern of cisplatin toxic effects was different among the ages and tissues of rats. The present study also revealed that newborn rats are more sensitive to treatment with cisplatin for at least the first 24 h and further showed that liver damage, at least in the beginning, was greater than renal damage in adult rats. Thus, the present study demonstrated that there are differences in the body response to acute exposure of cisplatin among adult and newborn rats, reinforcing the need for further studies on children response to chemotherapy and possible effective strategies to minimize the damage caused by cisplatin.A cisplatina é um quimioterápico amplamente utilizado para tratar diversos tipos de tumores, tanto em adultos quanto em crianças. Apesar de bastante difundido, o uso da cisplatina está relacionado a efeitos tóxicos graves, dentre eles a nefrotoxicidade e a hepatotoxicidade. Desta forma, a presente dissertação investigou os efeitos causados pela administração aguda de cisplatina em ratos com 10 dias e as diferenças na resposta ao fármaco, no que se refere à toxicidade, quando comparada a ratos de 60 dias. Para a realização deste modelo experimental foram utilizados ratos Wistar machos e fêmeas, com 10 e 60 dias (CEUA nº 2699300315). Os animais receberam a cisplatina nas doses de 5 e 10 mg/kg pela via intraperitoneal (i.p.), enquanto o grupo controle recebeu a solução salina (0,9%; i.p.). Após 24 h da administração de cisplatina/salina, os animais foram mortos e o sangue, o fígado e os rins foram coletados para as análises ex vivo. Nas amostras de soro foram avaliados os parâmetros de dano renal (ureia) e hepático (atividade das enzimas alanina aminotransferase, aspartato aminotransferase). Enquanto que nas amostras de fígado e rim foram determinados: os marcadores de estresse oxidativo (níveis de espécies reativas de oxigênio, peroxidação lipídica, carbonilação de proteínas e tióis não-proteicos (NPSH)); e as atividades das enzimas antioxidantes (superóxido dismutase, catalase (CAT), glutationa peroxidase, glutationa-S-transferase e glutationa redutase); assim como as atividades das enzimas sulfidrílicas δ-aminolevulinato desidratase (δ-ALA-D) e Na+, K+- ATPase. Os níveis renais e hepáticos das proteínas relacionadas com o estresse oxidativo e com a apoptose também foram determinados. A administração aguda de cisplatina causou toxicidade hepatorrenal em ratos recém-nascidos e adultos. No entanto, o padrão e a intensidade dos danos foram diferentes entre as idades e os tecidos. Os ratos recém-nascidos apresentaram um dano oxidativo mais acentuado em relação aos ratos adultos, caracterizado por um aumento nos níveis de espécies reativas e na proteína carbonila, um menor conteúdo de NPSH e uma maior inibição nas atividades da δ-ALA-D e CAT. Além disso, foi observada uma resposta molecular mais rápida nos níveis proteicos envolvidos com apoptose e resposta ao estresse oxidativo. Em conclusão, os dados deste estudo mostram que o padrão de efeitos tóxicos da cisplatina foi diferente entre as idades e os tecidos dos ratos. Além disso, o presente estudo revelou que os ratos recém-nascidos são mais sensíveis ao tratamento com a cisplatina, pelo menos nas primeiras 24 horas e ainda mostrou que, pelo menos no início, o dano hepático foi maior do que o renal em ratos adultos. Assim, o presente estudo demonstrou que existem diferenças na resposta corporal à exposição aguda da cisplatina entre ratos adultos e recém-nascidos, reforçando a necessidade de mais estudos sobre a resposta da criança à quimioterapia e possíveis estratégias efetivas para minimizar os danos causados pela cisplatina.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessCisplatinaNefrotoxicidadeHepatotoxicidadeEstresse oxidativoCisplatinNephrotoxicityHepatotoxicityOxidative stressCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICACisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultosCisplatin induces different hepatorrenal patern toxicity in neonate and adult ratsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisZeni, Gilson Rogériohttp://lattes.cnpq.br/2355575631197937Nogueira, Cristina Waynehttp://lattes.cnpq.br/2877042401245169Wilhelm, Ethel Antuneshttp://lattes.cnpq.br/2247558205680051Bochi, Guilherme Vargashttp://lattes.cnpq.br/4191221572795869http://lattes.cnpq.br/2849809788703333Fulco, Bruna da Cruz Weber200800000002600b21a898a-0ab0-4f33-b980-2b55ef590b944f18aa15-63e9-4416-ab46-ad07af264e94c2b1a64f-5f22-4779-9732-0c543f42b42dde3fb853-66dc-4631-a55d-d35e7962cc2e1c7110ce-ab6f-4049-a510-6896d577a65freponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGBT_2018_FULCO_BRUNA.pdfDIS_PPGBT_2018_FULCO_BRUNA.pdfDissertação de Mestradoapplication/pdf1480002http://repositorio.ufsm.br/bitstream/1/18788/1/DIS_PPGBT_2018_FULCO_BRUNA.pdf75ee3c7cb5588adbfcb943dc4f64be7eMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
dc.title.alternative.eng.fl_str_mv |
Cisplatin induces different hepatorrenal patern toxicity in neonate and adult rats |
title |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
spellingShingle |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos Fulco, Bruna da Cruz Weber Cisplatina Nefrotoxicidade Hepatotoxicidade Estresse oxidativo Cisplatin Nephrotoxicity Hepatotoxicity Oxidative stress CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
title_full |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
title_fullStr |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
title_full_unstemmed |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
title_sort |
Cisplatina induz um padrão de toxicidade hepatorrenal diferente em ratos neonatos e adultos |
author |
Fulco, Bruna da Cruz Weber |
author_facet |
Fulco, Bruna da Cruz Weber |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Zeni, Gilson Rogério |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2355575631197937 |
dc.contributor.advisor-co1.fl_str_mv |
Nogueira, Cristina Wayne |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/2877042401245169 |
dc.contributor.referee1.fl_str_mv |
Wilhelm, Ethel Antunes |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/2247558205680051 |
dc.contributor.referee2.fl_str_mv |
Bochi, Guilherme Vargas |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/4191221572795869 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2849809788703333 |
dc.contributor.author.fl_str_mv |
Fulco, Bruna da Cruz Weber |
contributor_str_mv |
Zeni, Gilson Rogério Nogueira, Cristina Wayne Wilhelm, Ethel Antunes Bochi, Guilherme Vargas |
dc.subject.por.fl_str_mv |
Cisplatina Nefrotoxicidade Hepatotoxicidade Estresse oxidativo |
topic |
Cisplatina Nefrotoxicidade Hepatotoxicidade Estresse oxidativo Cisplatin Nephrotoxicity Hepatotoxicity Oxidative stress CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Cisplatin Nephrotoxicity Hepatotoxicity Oxidative stress |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Cisplatin is a widely used chemotherapeutic to treat several types of tumors on both adult and pediatric subjects. Although cisplatin is widely used, its use is associated with serious toxic effects, including nephrotoxicity and hepatotoxicity. Thus, the present study investigated the effects caused by cisplatin acute administration on newborn Wistar rats and the differences in the drug toxicity compared to adult rats. The study was carried out using male and female Wistar rats 10 and 60 day-old (CEUA nº 2699300315). Rats received cisplatin at doses of 5 and 10 mg/kg, by the intraperitoneal (ip.) route, whereas the control group received saline (0.9%, ip.). After 24 h of cisplatin/saline administration, the animals were killed and samples of blood, liver, and kidneys were collected for ex vivo analyses. Markers of renal (urea) and hepatic damage (alanine aminotransferase and aspartate aminotransferase activities) were determined in the serum samples. Parameters of oxidative stress (levels of reactive oxygen species, lipid peroxidation, carbonyl protein, non-protein thiols (NPSH)); activities of antioxidant enzymes (superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione- S-transferase and glutathione reductase) and activities of sulfhydryl enzymes (δ-aminolevulinate dehydratase (δ-ALA-D) and Na +, K + - ATPase) were determined in samples of liver and kidney of rats. The levels of proteins related to oxidative stress and apoptosis were also determined in samples of liver and kidney of rats at both ages. The cisplatin acute administration caused hepatorenal toxicity in both neonatal and adult rats. However, the pattern and the severity of the damages were different among the ages and tissues. Newborn rats presented greater oxidative metabolic damage when compared to adult rats, characterized by an increase in reactive species and carbonyl protein levels, lower NPSH content, and greater inhibition of δ-ALA-D and CAT activities. In addition, a faster molecular response was found in the protein levels involved with apoptosis and response to oxidative stress. In conclusion, the data from this study show that the pattern of cisplatin toxic effects was different among the ages and tissues of rats. The present study also revealed that newborn rats are more sensitive to treatment with cisplatin for at least the first 24 h and further showed that liver damage, at least in the beginning, was greater than renal damage in adult rats. Thus, the present study demonstrated that there are differences in the body response to acute exposure of cisplatin among adult and newborn rats, reinforcing the need for further studies on children response to chemotherapy and possible effective strategies to minimize the damage caused by cisplatin. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018-07-20 |
dc.date.accessioned.fl_str_mv |
2019-11-04T19:04:40Z |
dc.date.available.fl_str_mv |
2019-11-04T19:04:40Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18788 |
url |
http://repositorio.ufsm.br/handle/1/18788 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
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UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
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