In situ formation of the acetaminophen metabolite covalently bound in kidney and lung Supportive evidence provided by total hepatectomy

Breen, Kerry J.; Joao-Carlos,; Wandscheer,; Peignoux, M; Pessayre, Dominique

doi:10.1016/0006-2952(82)90247-7

Cited by 34 publications

(11 citation statements)

References 7 publications

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“…Previous studies have demonstrated that the bronchial and bronchiolar epithelia [19–22], as well as the club cell within the bronchioles [11], express CYP2E1. Accordingly, following APAP exposure, APAP-protein adducts can be detected in the areas of the lung that express CYP2E1 [11, 15, 18, 23, 24]. These data support the hypothesis that pulmonary metabolism of APAP results in localized GSH depletion and accumulation of toxic metabolites resulting in injury to the large conducting airways.…”

Section: Introductionsupporting

confidence: 58%

Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung

Sandoval

Orlicky

Allawzi

et al. 2019

Oxidative Medicine and Cellular Longevity

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Clinical studies have demonstrated a strong association between both acute toxic exposure and the repetitive, chronic exposure to acetaminophen (APAP) with pulmonary dysfunction. However, the mechanisms underlying this association are unknown. Preclinical reports have demonstrated that significant bronchiolar injury occurs with toxic APAP exposure, but very little information exists on how the distal lung is affected. However, cells in the alveolar space, including the pulmonary epithelium and resident macrophages, express the APAP-metabolizing enzyme CYP2E1 and are a potential source of toxic metabolites and subsequent distal lung injury. Thus, we hypothesized that distal lung injury would occur in a murine model of toxic APAP exposure. Following exposure of APAP (280 mg/kg, IP), adult male mice were found to have significant proximal lung histopathology as well as distal lung inflammation and emphysematous changes. Toxic APAP exposure was associated with increased CYP2E1 expression in the distal lung and accumulation of APAP-protein adducts. This injury was associated with distal lung activation of oxidant stress, endoplasmic reticulum stress, and inflammatory stress response pathways. Our findings confirm that following toxic APAP exposure, distal lung CYP2E1 expression is associated with APAP metabolism, tissue injury, and oxidant, inflammatory, and endoplasmic reticulum signaling. This previously unrecognized injury may help improve our understanding of the relationship between APAP and pulmonary-related morbidity.

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Section: Introductionsupporting

confidence: 58%

Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung

Sandoval

Orlicky

Allawzi

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…It was concluded that this· tissue injury resulted from the activation of acetaminophen in situ to a chemical ly reactive species capable of covalently binding to tissue macromolecules . That the metabolic activation occurred in situ was demonstrated by Breen et al (102), who showed, that after administration of 3H-acetaminophen to rats, covalent binding occurred in both kidney and lung, and that the binding in these tissues was unaffected by total hepatectomy. Newton and co-workers (103) demonstrated a marked strain difference in rats in susceptibility to acetaminophen-produced renal damage.…”

Section: Acetaminophenmentioning

confidence: 88%

The Metabolism of Xenobiotics by Certain Extrahepatic Organs and its Relation to Toxicity*

Gram¹,

Okine²,

Gram³

1986

Annu. Rev. Pharmacol. Toxicol.

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“…Paraquat and bromobenzene produce necrosis of alveolar cells and Clara cells, respectively, after systemic exposure (6; 20, 26). The lungs, like many other organs of the body, contain measurable levels of cytochrome P-450 (3,4,20), and a recent report has shown that metabolites of acetaminophen can be formed in sitti within lung tissue and covalently bind to pulmonary cells (4). Also, tetrachloroethylene and xylene are readily metabolized by MFO enzymes, forming reactive species which produce pulmonary edema and cellular necrosis (20).…”

Section: Discussionmentioning

confidence: 99%

Extrahepatic Lesions Induced by Acetaminophen in the Mouse

1987

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Acetaminophen in acute overdose is primarily recognized as potentially hepatotoxic with few descriptions of extrahepatic lesions other than nephrotoxicity. Fasted adult, male mice, both standard and germ-free, were given acetaminophen orally and killed at selected times, from 30 minutes to 48 hours after treatment. In addition to the expected hepatic effects after 600 mg acetaminophenlkg, degenerative and necrotic changes were found in four non-hepatic tissues. Nephrosis developed 2 to 4 hours after treatment and paralleled the course of hepatic damage. Necrosis of bronchiolar epithelium in the absence of inflammation was evident 4 to 6 hours after acetaminophen administration as was onset of testicular changes. Spermatidic degeneration with early development of spermatidic multinucleated giant cells were characteristic features. Areas of lymphoid necrosis were also visible in splenic follicles and Peyer's patches 18 to 24 hours after treatment. These observations have demonstrated that other tissues in addition to liver and kidney are damaged by acetaminophen toxicity and should be considered in cases of acetaminophen overdosage.

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In situ formation of the acetaminophen metabolite covalently bound in kidney and lung Supportive evidence provided by total hepatectomy

Cited by 34 publications

References 7 publications

Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung

Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung

The Metabolism of Xenobiotics by Certain Extrahepatic Organs and its Relation to Toxicity*

Extrahepatic Lesions Induced by Acetaminophen in the Mouse

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