Rat liver endothelial and Kupffer cell-mediated mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1.

Steinberg, Pablo; Schlemper, B. R.; Molitor, Elvira; Platt, Karl L.; Seidel, Albrecht; Oesch, Franz

doi:10.1289/ehp.908871

Cited by 11 publications

(10 citation statements)

References 11 publications

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“…[27] Sinusoidal endothelial cells have been shown to possess cytochrome P450 activity [28] and to be targets of metabolic activation. [29] In addition, direct infusion of sources of superoxide and nitric oxide (i.e. the precursors of peroxynitrite) in an isolated perfused rat liver system resulted in morphological and structural alterations in liver sinusoids, consistent with the in vivo changes found in APAP toxicity.…”

Section: Resultsmentioning

confidence: 56%

Acetaminophen Toxicity in Mice Lacking NADPH Oxidase Activity: Role of Peroxynitrite Formation and Mitochondrial Oxidant Stress

James

McCullough

Knight

et al. 2003

Free Radical Research

137

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Previous data have indicated that activated macrophages may play a role in the mediation of acetaminophen toxicity. In the present study, we examined the significance of superoxide produced by macrophages by comparing the toxicity of acetaminophen in wild-type mice to mice deficient in gp91phox, a critical subunit of NADPH oxidase that is the primary source of phagocytic superoxide. Both groups of mice were dosed with 300 mg/kg of acetaminophen or saline and sacrificed at 1, 2, 4 or 24 h. Glutathione in total liver and in mitochondria was depleted by approximately 90% at 1 h in wild-type and knock out mice. No significant differences in toxicity (serum transaminase levels or histopathology) were observed between wild-type and mice deficient in gp91phox. Mitochondrial glutathione disulfide, as a percent of total glutathione, was determined as a measure of oxidant stress produced by increased superoxide, leading to hydrogen peroxide and/or peroxynitrite. The percent mitochondrial glutathione disulfide increased to approximately 60% at 1 h and 70% at 2 h in both groups of mice. Immunohistochemical staining for nitrotyrosine was present in vascular endothelial cells at 1 h in both groups of mice. Acetaminophen protein adducts were present in hepatocytes at 1 h in both wild-type and knock out animals. These data indicate that superoxide from activated macrophages is not critical to the development of acetaminophen toxicity and provide further support for the role of mitochondrial oxidant stress in acetaminophen toxicity.

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Section: Resultsmentioning

confidence: 56%

Acetaminophen Toxicity in Mice Lacking NADPH Oxidase Activity: Role of Peroxynitrite Formation and Mitochondrial Oxidant Stress

James

McCullough

Knight

et al. 2003

Free Radical Research

137

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“…Previous data indicated that hepatic endothelial cells contain CYP enzymes (Oesch and Steinberg 1987; Steinberg et al 1990), and that activation of acetaminophen by CYP enzymes in endothelial cells may produce toxicity. Endothelial cells were isolated from two strains of mice.…”

Section: Alterations In Hepatic Blood Flow In Acetaminophen Toxicitymentioning

confidence: 99%

Mechanisms of Acetaminophen-Induced Liver Necrosis

Hinson

Roberts²,

James³

2009

Handbook of Experimental Pharmacology

862

681

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Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.

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“…SECs have significant P450 activity and can metabolize drugs present in the portal circulation. [23][24][25] Metabolites exported across the sinusoidal pole of the hepatocyte enter the space of Disse, so that SECs may be exposed to higher concentrations of potentially toxic metabolites than are present in the hepatic vein or the systemic circulation. Because of this concentration gradient of toxic metabolites between the space of Disse and hepatic venous blood, SECs may be targeted by a mild toxic insult, whereas a more marked toxic insult is necessary to damage hepatic venular endothelial cells and endothelial cells in distant organs.…”

Section: Drug-induced Injury To Secsmentioning

confidence: 99%

Hepatic Microvasculature in Liver Injury

2007

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Injury to the hepatic microvasculature, the hepatic sinusoids, manifests in several ways. The sinusoidal endothelial cells (SECs) may lose porosity and scavenger function (capillarization); SECs may loosen from their tetherings to the space of Disse or even detach completely (ischemia-reperfusion injury, early sinusoidal obstruction syndrome, peliosis hepatis, early acetaminophen toxicity); the space of Disse may be completely denuded of sinusoidal lining cells that then embolize and obstruct the sinusoid (early sinusoidal obstruction syndrome); or the sinusoid may be obstructed by fibrosis (hepatic sinusoidal fibrosis, late sinusoidal obstruction syndrome). In many of these microvascular injuries, the change to the sinusoid is a primary event that may lead to hepatocyte hypoxia with liver dysfunction and disruption of the portal circulation. With the exception of hepatic fibrosis, which will be reviewed elsewhere in this issue, each of these types of microvascular injuries will be described in this article.

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Rat liver endothelial and Kupffer cell-mediated mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1.

Cited by 11 publications

References 11 publications

Acetaminophen Toxicity in Mice Lacking NADPH Oxidase Activity: Role of Peroxynitrite Formation and Mitochondrial Oxidant Stress

Acetaminophen Toxicity in Mice Lacking NADPH Oxidase Activity: Role of Peroxynitrite Formation and Mitochondrial Oxidant Stress

Mechanisms of Acetaminophen-Induced Liver Necrosis

Hepatic Microvasculature in Liver Injury

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