Acetaminophen-arylated proteins are detected in hepatic subcellular fractions and numerous extra-hepatic tissues in CD-1 and C57B1/6J mice

Bulera, Steven J.; Cohenb, S.D.; Khairallah, Edward A.

doi:10.1016/0300-483x(96)03309-4

Cited by 31 publications

(25 citation statements)

References 40 publications

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“…5,36,37 Besides hepatotoxicity, prior studies have indicated the renal damage in APAP affected humans 59 as well as animals. 60,61 What was also reported was the degenerative and necrotic changes of lymphoid nodes in APAP treated mice.…”

Section: Resultsmentioning

confidence: 99%

“…60,61 What was also reported was the degenerative and necrotic changes of lymphoid nodes in APAP treated mice. 62 More prevalent effects have been observed by monitoring APAP-protein adducts 34,37 and the uptake of radioactive iodine-131-labeled APAP 35 in mouse tissues and organs, such as the kidney, lung, pancreas, heart, skeletal muscle, stomach, and certain regions of the brain. Our proteomic observation matches well with these reports.…”

Section: Resultsmentioning

confidence: 99%

“…5,36,37 These approaches obviously cannot be applied to human studies. In clinics, noninvasive assays used to assess organ damage caused by overdosing APAP include the transaminases ALT and AST (also known as SGPT and SGOT) tests for the liver and the BUN (blood urea nitrogen) and creatinine tests for the kidney.…”

Section: Introductionmentioning

confidence: 99%

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Glycocapture-Assisted Global Quantitative Proteomics (gagQP) Reveals Multiorgan Responses in Serum Toxicoproteome

Sun

Utleg

et al. 2013

J. Proteome Res.

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Blood is an ideal window for viewing our health and disease status. Because blood circulates throughout the entire body and carries secreted, shed, and excreted signature proteins from every organ and tissue type, it is thus possible to use the blood proteome to achieve a comprehensive assessment of multiple-organ physiology and pathology. To date, the blood proteome has been frequently examined for diseases of individual organs; studies on compound insults impacting multiple organs are, however, elusive. We believe that a characterization of peripheral blood for organ-specific proteins affords a powerful strategy to allow early detection, staging, and monitoring of diseases and their treatments at a whole-body level. In this paper we test this hypothesis by examining a mouse model of acetaminophen (APAP)-induced hepatic and extra-hepatic toxicity. We used a glycocapture-assisted global quantitative proteomics (gagQP) approach to study serum proteins and validated our results using Western blot. We discovered in mouse sera both hepatic and extra-hepatic organ-specific proteins. From our validation, it was determined that selected organ-specific proteins had changed their blood concentration during the course of toxicity development and recovery. Interestingly, the peak responding time of proteins specific to different organs varied in a time-course study. The collected molecular information shed light on a complex, dynamic, yet interweaving, multiorgan-enrolled APAP toxicity. The developed technique as well as the identified protein markers is translational to human studies. We hope our work can broaden the utility of blood proteomics in diagnosis and research of the whole-body response to pathogenic cues.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Glycocapture-Assisted Global Quantitative Proteomics (gagQP) Reveals Multiorgan Responses in Serum Toxicoproteome

Sun

Utleg

et al. 2013

J. Proteome Res.

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“…On the other hand, in the kidney and nasal mucosa, the extent of acetaminophen-induced NPSH depletion was similar in the Null and wild-type mice. Acetaminophen-protein adducts were not detected in these tissues under the conditions used with the anti-acetaminophen (4-acetamidobenzoic acid) polyclonal antibody (Matthews et al, 1996), although acetaminophen protein adducts were detected in the kidney in a previous study in which a 125 I-conjuagted secondary antibody was used for immunoblot analysis (Bulera et al, 1996). The apparently low abundance of acetaminophen-protein adducts in the kidney and nasal mucosa, tissues that were sustaining damage in the acetaminophen-treated wild-type mice, suggests that protein adduction with acetaminophen is not a major route of acetaminophen toxicity in these organs.…”

Section: Mechanisms Of Extrahepatic Acetaminophen Toxicity 627mentioning

confidence: 93%

In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

et al. 2004

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Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wildtype mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.

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“…An earlier study conducted in vivo, which used the same dose of APAP as our study showed that NAPQI does not bind to protein in the brain. However, this study was realized only in the cytosolic fraction and not in mitochondria (Bulera et al 1996) as we studied here. Therefore, we believe that NAPQI may bind to brain mitochondrial protein, similar to what occurs in the liver (Bulera et al 1996), though more studies are needed to identify the exact mechanism by which APAP causes toxicity in brain mitochondria.…”

Section: Discussionmentioning

confidence: 85%

Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

et al. 2011

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Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activities, with potential pharmacological and therapeutic applications. The aim of this study was to investigate the effect of diphenyl diselenide (PhSe)(2) in reversing oxidative brain damage and mitochondrial dysfunction caused by administration of acetaminophen (APAP) in mice. Mice received a toxic dose of APAP, followed by a dose of (PhSe)(2) 1 h later. Four hours after the administration of APAP, plasma was withdrawn from the mice and used for biochemical assays of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatotoxicity. Brain homogenate was examined to determine oxidative stress. Isolated brain mitochondria were examined to quantify mitochondrial transmembrane's electrical potential and mitochondrial swelling and to estimate reactive oxygen species (ROS) production. APAP administration caused an increase in plasma ALT and AST activities. APAP administration also caused a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and dichlorofluorescein oxidation in brain homogenate. Similarly, mitochondrial swelling and ROS production increased after APAP administration. APAP treatment also caused a decrease in Na(+), K(+)- ATPase activity and in mitochondrial membrane potential. These alterations observed in the brain of APAP-treated mice were restored by (PhSe)(2). Glutathione levels were decreased by APAP, but (PhSe)(2) did not reverse this change. Treatment with (PhSe)(2) after APAP administration can reverse the neurotoxicity caused by a single toxic dose of APAP. The neuroprotective effect of (PhSe)(2) is likely associated with its antioxidant properties.

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Acetaminophen-arylated proteins are detected in hepatic subcellular fractions and numerous extra-hepatic tissues in CD-1 and C57B1/6J mice

Cited by 31 publications

References 40 publications

Glycocapture-Assisted Global Quantitative Proteomics (gagQP) Reveals Multiorgan Responses in Serum Toxicoproteome

Glycocapture-Assisted Global Quantitative Proteomics (gagQP) Reveals Multiorgan Responses in Serum Toxicoproteome

In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

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