Hepatotoxicity of mild analgesics.

Prescott, L. F.

doi:10.1111/j.1365-2125.1980.tb01825.x

Cited by 57 publications

(35 citation statements)

References 39 publications

(41 reference statements)

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“…As a result, this reactive metabolite binds covalently to cellular macromolecules 8 leading to a potentially fatal centrilobular hepatic necrosis. 9 Pretreatment with per os D-glucose in mice treated with a sublethal dose of APAP (300 mg/kg) succeeded in preserving a normal liver morphology and maintaining circulating ALT and LDH levels comparable with control mice. The same treatment rescued from death 100% of mice treated with a lethal dose of APAP (1125 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

“…8 This can lead to a potentially fatal centrilobular hepatic necrosis. 9 On the other hand, ␣-amanitin toxin, which provide the major morbidity and mortality associated with toxic mushroom ingestion, interact with RNA polymerase II and affected cells undergo apoptosis due to insufficient protein synthesis. Organs mainly affected by ␣-amanitin include the intestinal mucosa, hepatocytes, and proximal tubules of kidney.…”

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confidence: 99%

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Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Zanobbio

Palazzo

Gariboldi

et al. 2009

The American Journal of Pathology

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Superiore di Sanità, Rome; and the Istituto Nazionale per lo Studio e la Cura dei Tumori, ‡ Milan, ItalyWe have recently observed that oral administration of D-glucose saves animals from lipopolysaccharide (LPS)-induced death. This effect is the likely consequence of glucose-induced activation of the sodiumdependent glucose transporter-1. In this study, we investigated possible hepatoprotective effects of glucose-induced, sodium-dependent, glucose transporter-1 activation. We show that oral administration of D-glucose , but not of either D-fructose or sucrose, prevents LPS-induced liver injury, as well as liver injury and death induced by an overdose of acetaminophen. In both of these models, physiological liver morphology is maintained and organ protection is confirmed by unchanged levels of the circulating markers of hepatotoxicity, such as alanine transaminase or lactate dehydrogenase. In addition, D-glucose was found to protect the liver from ␣-amanitin-induced liver injury. In this case, in contrast to the previously described models, a second signal had to be present in addition to glucose to achieve protective efficacy. Toll-like receptor 4 stimulation that was induced by low doses of LPS was identified as such a second signal. Eventually, the protective effect of orally administered glucose on liver injury induced by LPS, overdose of acetaminophen, or ␣-amanitin was shown to be mediated by the anti-inflammatory cytokine interleukin-10. Liver failure is one of the most devastating syndromes observed in clinical practice. It is associated with high overall mortality, ranging from 30% to 80%, depending on the underlying etiology. 1,2 The most common etiologies are acute viral hepatitis, drug overdose, idiosyncratic drug reactions, and ingestion of other toxins.3 Insulting agents can cause hepatocyte death through different mechanisms of action, and when the amount of functioning cells decreases to a level at which the organ is no longer capable of fulfilling its metabolic and synthetic tasks, hepatic failure takes place. 4 Recently we demonstrated, in a murine model of septic shock, that oral administration of D-glucose saves mice from death, most likely as a result of glucose-induced activation of the intestinal sodium-dependent glucose transporter-1 (SGLT-1).5 Using this model, we made preliminary observations that the liver, one of the organs most severely affected by lipopolysaccharide and D-galactosamine (LPS/D-GalN) treatment, was protected by oral administration of D-glucose. The expression of SGLT-1 on the apical membrane of enterocytes and the observation that protection from LPS shock was observed only on oral administration of D-glucose, but not on i.p. administration, suggested an important role of intestinal epithelial cells in protection from LPS-induced injury to the liver and other organs.Here, we report on a more extensive investigation on the hepatoprotective effect of orally administered D-glucose. Glucose was evaluated in LPS-induced shock, as well as in two other models of acute liver f...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Zanobbio

Palazzo

Gariboldi

et al. 2009

The American Journal of Pathology

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“…Although considered safe at therapeutic doses, in overdose, acetaminophen produces a centrilobular hepatic necrosis that can be fatal (Prescott, 1980). Whereas the initial biochemical and metabolic events that occur in the early stages of toxicity have been well described, the precise mechanisms of hepatocyte death are poorly understood.…”

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confidence: 99%

Acetaminophen-Induced Hepatotoxicity

James¹,

Mayeux²,

Hinson³

2003

Drug Metab Dispos

890

683

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1␤ is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.

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“…Los AINE se identificaron como un grupo importante que puede causar alteraciones hepáticas (1, 72) principalmente de tipo idiosincrásico (73), en casos de abuso o sobredosis (74). Algunos factores de riesgo identificados fueron la edad, género femenino, consumo crónico de alcohol, fármacos concomitantes, enfermedades subyacentes, obesidad, DM2 y resistencia a la insulina (72).…”

Section: Discussionunclassified

Toxicidad hepática causada por medicamentos: revisión estucturada

P²,

Amariles

2017

Rev. Colomb. Gastroenterol.

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ResumenObjetivos: elaborar un listado actualizado de medicamentos causantes de hepatotoxicidad e identificar, de acuerdo con la evidencia científica, los medicamentos con mayor probabilidad de causar hepatotoxicidad. Método: se realizó una búsqueda en PubMed/Medline utilizando términos Mesh: "liver disease" y "druginduced liver injury". La búsqueda se filtró por: reportes de casos, revisiones, ensayos clínicos, metaanálisis y cartas, hasta diciembre de 2015, en inglés, español y francés. Se incluyeron artículos con evidencia de hepatotoxicidad causada por medicamentos y referencias relevantes; fueron excluidos artículos sin relación con los objetivos de la búsqueda, relacionados con hepatotoxicidad por agentes diferentes, concernientes a otras causas de enfermedad hepática o relacionados con ensayos predictivos o células madre. Algunos aspectos de los medicamentos hepatotóxicos fueron: aparición de hepatotoxicidad, tipo de lesión, mecanismos de hepatotoxicidad, factores de riesgo y manifestaciones clínicas. Para valorar la probabilidad de aparición de hepatotoxicidad y del tipo de lesión se establecieron 3 categorías: definida, probable y posible. Resultados: se identificaron 610 artículos de los cuales se eligieron 402, se excluyeron 208 artículos. Se elaboró un listado con 181 medicamentos y 17 formas farmacéuticas combinadas o regímenes terapéuticos con probabilidad de causar hepatotoxicidad; de estos, 6 medicamentos tuvieron probabilidad definida (metotrexato, minociclina, vancomicina, everolimus, isoniazida y tamoxifeno). Conclusiones: se identificaron más de 180 medicamentos hepatotóxicos, 6 tienen una probabilidad definida, mientras que para la mayoría es posible. La consolidación de la información demostró que diversas categorías de medicamentos tienen mayor probabilidad de ser causantes de hepatotoxicidad. Palabras claveEnfermedad hepática, daño hepático inducido por medicamentos. Revisión de tema

show abstract

Hepatotoxicity of mild analgesics.

Cited by 57 publications

References 39 publications

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Acetaminophen-Induced Hepatotoxicity

Toxicidad hepática causada por medicamentos: revisión estucturada

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