Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity

Donnelly, Patty J.; Walker, Robin M.; Racz, William J.

doi:10.1007/s002040050043

Cited by 112 publications

(63 citation statements)

References 29 publications

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“…Total RNA from liver tissue was prepared using the guanidinium phenol/chloroform method. 33 RNA (5 µg) was transcribed into complementary DNA using Moloney Murine Leukemia Virus reverse transcriptase (Life Technologies, Gaithersburg, MD) and oligodeoxythymidylic acid [12][13][14][15][16][17][18] . 34 Cytokine Reverse-Transcription Polymerase Chain Reaction.…”

Section: Methodsmentioning

confidence: 99%

“…Metabolic activation 5 of APAP and subsequent binding of its electrophilic metabolite N-acetyl-p-benzoquinone imine (NAPQI) to glutathione (GSH) and, after GSH depletion, to nucleophilic protein targets 6 seems to be necessary but is not sufficient for toxicity. 4,7 Several other mechanistic components of parenchymal cell injury have been proposed, including the generation of reactive oxygen species, [8][9][10][11] mitochondrial dysfunction [12][13][14] followed by disruption of calcium homeostasis and energy supply, or induction of apoptosis. 15 Apart from these events occurring intracellularly in parenchymal cells after APAP exposure, an important role has been attributed to nonparenchymal cells.…”

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confidence: 99%

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Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-␣ (LT-␣). Male TNF/LT-␣ knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-␣-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-␣ were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-␣, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity. (HEPATOLOGY 1998;27:1021-1029.)

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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“…Aparte de este mecanismo oxidativo, se han propuesto experimentalmente otras vías fisiopatológicas complementarias o, incluso, determinantes del daño hepático y extrahepático: formación de radicales libres 12 , cambios isquémicos en la microcirculación 13 , trastornos de la homeostasis cálcica 14 , inhibición de la cadena respiratoria mitocondrial 15 , etc.…”

Section: Mecanismo De Acciónunclassified

Intoxicaciones medicamentosas (II): Analgésicos y anticonvulsivantes

Munné

Banuelos

Izura

et al. 2003

Anales Sis San Navarra

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RESUMENEn este segundo capítulo sobre Intoxicaciones Medicamentosas Agudas abordamos dos grupos de sustancias de enorme trascendencia desde el punto de vista de su uso y morbimortalidad. Dentro del grupo de los anagésicos-antiinflamatorios desarrollamos el paracetamol y los salicilatos, de enorme disponibilidad para la población. En cuanto a los anticonvulsivantes, aunque están poco implicados en el conjunto de las intoxicaciones medicamentosas agudas, sus efectos pueden ser graves. Nos ceñimos a cuatro fármacos: ácido valproico, fenobarbital, carbamacepina, y fenitoína. Finalmente dedicamos un apartado a la isoniacida, fármaco que, con el rebrote de la tuberculosis, presenta interés toxicológico.Palabras clave. Intoxicación aguda. Paracetamol. Anticonvulsivantes. Fenitoína. Isoniacida. ABSTRACTIn this second chapter on Acute Drugs Poisoning we deal with two groups of substances of great transcendence from the point of view of their use and morbidity/mortality. Within the group of analgesic-antiinflammatory drugs we consider paracetamol and the salicylates, which are easily available to the population. With respect to the anticonvulsants, although they are barely involved in the ensemble of acute drug poisonings, their effects can be serious. We concentrate on four drugs: valproic acid, phenobarbitol, carbamacepine, and phenytoin. Finally, a section is dedicated to isoniazid, a drug that, with the renewed incidence of tuberculosis, is of toxicological interest.

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“…An overdose of paracetamol has a toxic effect, which causes liver injury both in experimental animals and humans. Its toxicity has been shown to be initiated by cytochrome P450 metabolism to N-acetyl-p-benzoquinone imine (NAPQI) (1). The most common cause of acute liver failure worldwide is paracetamol, which is usually a nonprescribed drug.…”

Section: Introductionmentioning

confidence: 99%

The protective effect of Capparis ovata in acute hepatotoxicity induced by paracetamol

et al. 2016

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Background/aim: To investigate the efficiency of Capparis ovata as a protective agent against acute paracetamol toxicity of the liver. Materials and methods:A total of 36 Wistar albino rats were divided into 4 groups: 1) paracetamol, 2) Capparis ovata + paracetamol, 3) Capparis ovata, and 4) control. Groups 2 and 3 were given Capparis ovata and Groups 1 and 4 distilled water for 8 days. On day 8, 3000 mg kg -1 paracetamol was administered orally to Groups 1 and 2. Samples were taken on day 9. AST, ALT, total bilirubin, direct bilirubin, GGT, and ALP levels were assessed. Lipid peroxidation markers and thiobarbituric acid-reactive substance (TBARS) levels were measured in the blood and liver. Liver tissues were evaluated histologically.Results: AST, ALT, and total bilirubin levels were lower in Group 2 than in Group 1 (P < 0.05). TBARS levels were lower in Groups 2 (P = 0.000), 3 (P = 0.001), and 4 (P = 0.001) than in Group 1. Degenerative findings were lower in the Capparis ovata + paracetamol group than in the paracetamol group (P < 0.05). Conclusion:It can be concluded that Capparis ovata has a protective effect on the liver, both histopathologically and biochemically, against paracetamol-induced liver injury.

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Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity

Cited by 112 publications

References 29 publications

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Intoxicaciones medicamentosas (II): Analgésicos y anticonvulsivantes

The protective effect of Capparis ovata in acute hepatotoxicity induced by paracetamol

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