The Role of Hypoxia-Inducible Factor-1α in Acetaminophen Hepatotoxicity

Sparkenbaugh, Erica; Saini, Yogesh; Greenwood, Krista K.; LaPres, John J.; Luyendyk, James P.; Copple, Bryan L.; Maddox, Jane F.; Ganey, Patricia E.; Roth, Robert A.

doi:10.1124/jpet.111.180521

Cited by 38 publications

(27 citation statements)

References 40 publications

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“…Furthermore, reoxygenation following hypoxic ischemia may also contribute to mitochondrial dysfunction and liver injury, as described (Moon, Hood, et al, 2008). Hypoxia-related liver injury due to CYP2E1-dependent metabolism of its potentially toxic substrates such as APAP, halothane, and CCL4 can be also observed in acute DILI, as reported ( James, Donahower, Burke, McCullough, & Hinson, 2006;Noll & De Groot, 1984;Sparkenbaugh et al, 2011). However, Lieber (2005) suggested that APAP-induced liver injury could be worse during alcohol withdrawal, due to less competition by alcohol for the CYP2E1-dependent metabolism of APAP.…”

Section: Role and Regulation Of Cyp2e1 In Liver Diseasementioning

confidence: 81%

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Song

Akbar

et al. 2015

Advances in Pharmacology

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Section: Role and Regulation Of Cyp2e1 In Liver Diseasementioning

confidence: 81%

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Song

Akbar

et al. 2015

Advances in Pharmacology

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“…It is likely that the cellular mechanisms used by acetaminophen to produce toxicity may, in a lower dose range, mediate its therapeutic effects. In this regard, toxicity resulting from high dose acetaminophen is in part mediated by thrombin (Ganey et al, 2007; Sparkenbaugh et al, 2011). Thus, we explored whether thrombin is a mediator of acetaminophen’s beneficial effects on brain endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Age-related decrease in cerebrovascular-derived neuroprotective proteins: Effect of acetaminophen

Tripathy

Sanchez

Yin

et al. 2012

Microvascular Research

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As the population ages, the need for effective methods to maintain brain function in older adults is increasingly pressing. Vascular disease and neurodegenerative disorders commonly co-occur in older persons. Cerebrovascular products contribute to the neuronal milieu and have important consequences for neuronal viability. In this regard vascular derived neuroprotective proteins, such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and pituitary adenylate cyclase activating peptide (PACAP) are important for maintaining neuronal viability, especially in the face of injury and disease. The objective of this study is to measure and compare levels of VEGF, PEDF and PACAP released from isolated brain microvessels of Fischer 344 rats at 6, 12, 18, and 24 months of age. Addition of acetaminophen to isolated brain microvessels is employed to determine whether this drug affects vascular expression of these neuroprotective proteins. Experiments on cultured brain endothelial cells are performed to explore the mechanisms/mediators that regulate the effect of acetaminophen on endothelial cells. The data indicate cerebrovascular expression of VEGF, PEDF and PACAP significantly decreases with age. The age-associated decrease in VEGF and PEDF is ameliorated by addition of acetaminophen to isolated brain microvessels. Also, release of VEGF, PEDF, and PACAP from cultured brain endothelial cells decreases with exposure to the oxidant stressor menadione. Acetaminophen treatment upregulates VEGF, PEDF and PACAP in brain endothelial cells exposed to oxidative stress. The effect of acetaminophen on cultured endothelial cells is in part inhibited by the selective thrombin inhibitor hirudin. The results of this study suggest that acetaminophen may be a useful agent for preserving cerebrovascular function. If a low dose of acetaminophen can counteract the decrease in vascular-derived neurotrophic factors evoked by age and oxidative stress, this drug might be useful for improving brain function in the elderly.

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“…Acetaminophen hepatotoxicity has also been associated with HIF-1α activation, secondary to ROS formation (Chaudhuri et al 2011). Interestingly, HIF-1α-deficient mice exhibit attenuated acetaminophen hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1α is involved in the early stage of APAP toxicity, but protective at later time points (Sparkenbaugh et al 2011). Several other hepatotoxins, including amiodarone, diclofenac, troglitazone, and cyclosporine A, increase glycolysis and subsequent lactate production in cultured liver cells, (Limonciel et al 2011), a process that may be linked to HIF-1α activation.…”

Section: Hif-1α Pathwaymentioning

confidence: 96%

SEURAT-1 liver gold reference compounds: a mechanism-based review

et al. 2014

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There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for 'Safety Evaluation Ultimately Replacing Animal Testing.' The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation.

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The Role of Hypoxia-Inducible Factor-1α in Acetaminophen Hepatotoxicity

Cited by 38 publications

References 40 publications

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Age-related decrease in cerebrovascular-derived neuroprotective proteins: Effect of acetaminophen

SEURAT-1 liver gold reference compounds: a mechanism-based review

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