The role of the liver in the production of free radicals during halothane anaesthesia in the rat. Quantification of <i>N-tert</i>-butyl-alpha-(4-nitrophenyl)nitrone (PBN)-trapped adducts in bile from halothane as compared with carbon tetrachloride

Hughes, Helen MacGill; George, I M; Evans, Jeffrey; Rowlands, Christopher C.; Powell, Gavin; Curtis, C. G.

doi:10.1042/bj2770795

Cited by 16 publications

(2 citation statements)

References 34 publications

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“…Durante a reprodução não houve qualquer perda de animais, adicionalmente o modelo necessitou de apenas 10 dias para ser completado. Esses dois aspectos representam vantagem em relação a outros modelos animais de lesão oxidativa hepática (8,9,10) .…”

Section: Discussionunclassified

Modelo experimental de indução de lesão oxidativa hepática em ratos por halotano

Brasil

Amaral

Zettler

et al. 2007

Arq. Gastroenterol.

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RESUMO -Racional -O anestésico halotano pode ser metabolizado redutivamente a intermediários reativos que podem iniciar a lipoperoxidação acompanhada de injúria hepática. O tratamento prévio com hipóxia e fenobarbital em ratos aumenta o metabolismo do halotano e o estresse oxidativo e causa mudanças nas enzimas antioxidantes no fígado com dano hepático. INTRODUÇÃOMuitos pesquisadores têm dedicado esforços para elucidar os mecanismos subjacentes à lesão hepática provocada pelo anestésico halotano. Demonstrou-se a formação de espécies reativas de oxigênio in vivo após a exposição ao halotano pela espectroscopia paramagnética eletrônica (9) ou pela quantificação de fluorino sub 2-isoprostanos (1) . No entanto, a formação de radicais derivados de lipídios tem sido controversa (10) ou não observada (18) . Vários estudos têm indicado que a hipóxia aumenta a ligação de metabólitos do halotano a componentes da fração microssomal hepática (16) .Em um estudo, ratos com indução enzimática prévia, foram expostos por 2 horas, a concentrações de O 2 de 14% e halotano 1%, resultando com necrose centro-lobular em 24 h (fenobarbital 1 mg/mL na água de beber), por 10 dias antes do evento (14) . Esses resultados suportam a hipótese de que o halotano é metabolizado até intermediários hepatotóxicos em um modelo associado ao citocromo p-450 redutivo ou não-dependente de O 2 . LIND et al. (11) demonstraram que o grau de hepatotoxicidade máxima determinada por alterações morfológicas e atividade de ALT correlaciona-se com a concentração de halotano e de citocromo P-450 hepático.Existem vários modelos animais que reproduzem lesão oxidativa hepática, a maioria possui alta mortalidade e tempo gasto para seu êxito em relação ao modelo com halotano. Dentre os agentes etiológicos utilizados destacam-se o álcool, o tetracloreto de carbono e a ligadura de canal biliar (5,13,19) .O objetivo do presente trabalho foi confirmar se o halotano causa peroxidação lipídica e alteração nas enzimas antioxidantes in vivo em curto período de tempo e pode, portanto, ser utilizado como modelo experimental de lesão oxidativa hepática. Determinaram-se os efeitos do fenobarbital, da hipóxia e do halotano separadamente nesse processo. Finalmente, determinou-se se a peroxidação lipídica é acompanhada de injúria hepática (alterações estruturais e de aminotransferases hepáticas). MÉTODOSForam utilizados ratos machos, Wistar, com peso entre 250 e 350 g, provenientes do Biotério do Instituto

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Section: Discussionunclassified

Modelo experimental de indução de lesão oxidativa hepática em ratos por halotano

Brasil

Amaral

Zettler

et al. 2007

Arq. Gastroenterol.

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“… 14 , 15 However, due to their better distribution within tissues and cells, linear nitrones have been widely used for radical detection in ex vivo and in vivo studies. 16 − 18 Linear nitrones are usually easier to synthesize and purify as they are often solid at room temperature and can be recrystallized to afford paramagnetic impurity-free samples. Moreover, linear PBN-type nitrones allow the possibility of rather easy functionalization both on the aromatic ring and on the N - tert -butyl group and therefore provide more chemical versatility.…”

Section: Introductionmentioning

confidence: 99%

Para-Substituted α-Phenyl-N-tert-butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties

et al. 2020

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In this work, a series of para-substituted α-phenyl-N-tert-butyl nitrones (PBN) were studied. Their radical-trapping properties were evaluated by electron paramagnetic resonance, with 4-CF 3 -PBN being the fastest derivative to trap the hydroxymethyl radical ( • CH 2 OH). The redox properties of the nitrones were further investigated by cyclic voltammetry, and 4-CF 3 -PBN was the easiest to reduce and the hardest to oxidize. This is due to the presence of the electron-withdrawing CF 3 group. Very good correlations between the Hammett constants (σ p ) of the substituents and both spin-trapping rates and redox potentials were observed. These correlations were further supported by computationally determined ionization potentials and atom charge densities. Finally, the neuroprotective effect of these derivatives was studied using two different in vitro models of cell death on primary cortical neurons injured by glutamate exposure or on glial cells exposed to t BuOOH. Trends between the protection afforded by the nitrones and their lipophilicity were observed. 4-CF 3 -PBN was the most potent agent against t BuOOH-induced oxidative stress on glial cells, while 4-Me 2 N-PBN showed potency in both models.

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Excretion of F2-isoprostanes in bile: A novel index of hepatic lipid peroxidation

Awad

Morrow

1995

Hepatology

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Lipid peroxidation is believed to be an important mechanism of liver injury caused by some xenobiotics. However, it has been difficult to demonstrate and quantify this process in vivo. Moreover, little is known about the disposition of lipids oxidized in the liver. F2-isoprostanes are prostanoids produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid esterified to phospholipids. Hydrolysis of F2-isoprostanes from phospholipids by phospholipases yields free F2-isoprostanes. Excretion of F2-isoprostanes, both free and esterified to phospholipids, was measured in bile after administration of CCl4. The concentration of lipid-esterified F2-isoprostanes in bile exceeded that of free F2-isoprostanes. CCl4 caused a dose-dependent increase in biliary F2-isoprostane excretion that correlated better with the increase in liver F2-isoprostanes than it did with the increase in plasma F2-isoprostanes. Pretreatment with colchicine ameliorated CCl4-liver injury but did not affect baseline or CCl4-induced biliary F2-isoprostane excretion. Administration of diquat to selenium-deficient rats, which causes hepatic and renal necrosis, was associated with a 13-fold elevation of plasma F2-isoprostanes. However, both hepatic F2-isoprostane concentrations and biliary F2-isoprostane excretion were increased only threefold. These data suggest that quantification of F2-isoprostane excretion in bile may provide a sensitive and quantitative index of hepatic lipid peroxidation.

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The role of the liver in the production of free radicals during halothane anaesthesia in the rat. Quantification of N-tert-butyl-alpha-(4-nitrophenyl)nitrone (PBN)-trapped adducts in bile from halothane as compared with carbon tetrachloride

Cited by 16 publications

References 34 publications

Modelo experimental de indução de lesão oxidativa hepática em ratos por halotano

Modelo experimental de indução de lesão oxidativa hepática em ratos por halotano

Para-Substituted α-Phenyl-N-tert-butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties

Excretion of F2-isoprostanes in bile: A novel index of hepatic lipid peroxidation

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