Mechanisms of Acetaminophen-Induced Liver Necrosis

Hinson, Jack; Roberts, Dean W.; James, Laura P.

doi:10.1007/978-3-642-00663-0_12

Cited by 862 publications

(737 citation statements)

References 203 publications

(298 reference statements)

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“…1 The combination of these phenomena culminates in generalized oncotic necrosis and liver dysfunction. In fact, APAP poisoning is the most frequent etiology of drug-induced liver injury (DILI), which can progress to acute liver failure (ALF), a disorder associated with high mortality and hospitalization costs.…”

mentioning

confidence: 99%

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Marques¹,

Amaral²,

Pires³

et al. 2012

Hepatology

290

269

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Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9 2/2 mice). Conclusion: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.

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mentioning

confidence: 99%

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Marques¹,

Amaral²,

Pires³

et al. 2012

Hepatology

290

269

View full text Add to dashboard Cite

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“…The mechanism of hepatotoxicity caused by acetaminophen is unknown, however, there is a massive production of oxygen free radicals and a direct cytotoxic effect involved in the pathogenesis of this lesion, with a consequent necrosis and apoptosis of the hepatocytes 17,18 .…”

Section: Discussionmentioning

confidence: 99%

Attenuation of copaiba oil in hepatic damage in rats

et al. 2014

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“…30 APAP exposure led to a time and dose-dependent increase in LDH-release (Figure 2a), suggesting cytochromemediated generation of toxic metabolites. By measurement of free thiols, we found in parallel to the mechanism described in hepatocytes a decrease in thiols in MH cell after APAP exposure (Figure 2b).…”

Section: Mh Cells Are Susceptible To Hepatotoxic Drugs and Drug Intermentioning

confidence: 99%

Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies

Benesic

Rahm

Ernst

et al. 2012

Laboratory Investigation

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Gender, ethnicity and individual differences in hepatic metabolism have major impact on individual drug response, adverse events and attrition rate during drug development. Therefore, there is an urgent need for reliable test systems based on human cells. Yet, the use of primary human hepatocytes (PHHs) is restricted by limited availability, invasive preparation and short-term stability in culture. All other cellular approaches proposed so far have major disadvantages. We investigated whether peripheral human monocytes after cultivation according to our novel protocol (monocyte-derived hepatocyte-like cells (MH cells)) can serve as an in vitro model for hepatocyte metabolism. Enzyme activities, synthesis parameters (coagulation factor VII and urea) and cytochrome (CY) P450 activities and induction were investigated. Furthermore, MH cells were compared with PHH from the same donor. Using our protocol, we could generate cells that exhibit hepatocyte-like properties: These cells show 71±9% of specific ALT activity, 41±3% of CYP3A4 activity and 65±13% of factor VII secretion when compared with PHHs. Consequently, CYP-mediated acetaminophen toxicity and drug interactions could be shown. Moreover, the investigated parameters were stable in culture over at least 4 weeks. Furthermore, MH cells retain gender-specific and donor-specific CYP activities and toxicity profiles, respectively. MH cells show quantitative and qualitative approximation to human hepatocytes concerning CYP-metabolism and toxicity. Our data support individual prediction of toxicity and CYP metabolism. MH cells are a novel tool to investigate long-term hepatic toxicity, metabolism and drug interactions. The liver is an important site of drug metabolism and hepatocytes are mainly responsible for toxification and detoxification of substances. A huge array of enzymes and transporters allows the hepatocyte to metabolize, conjugate and finally excrete xenobiotics and endobiotics. The first step, also referred to as phase-I metabolism, is performed predominantly by enzymes of the cytochrome P450 (CYP450) enzyme family. The CYPs 1A2, 2A6, 2B6, 2D6, 2E1, 3A4 and 3A5 are found in hepatocytes with great abundance. 1 Most CYP enzymes can be induced, that is, their activity in the hepatocyte is increased to manage greater amounts of xenobiotics. This induction is mediated by receptors, such as the pregnane-X-receptor (PXR), 2 the aryl-hydrocarbon receptor 3 and the constitutive androestendione receptor. 1 Knowing the way a substance is metabolized and how a substance interacts with co-medication is crucial for modern drug design. Therefore, hepatocyte models are urgently needed for drug development, because no other cell possesses a comparable equipment of metabolism pathways. The complexity of this system is augmented by different activities of CYP enzymes dependent on sex, age, ethnicity and individual factors, including co-medication. [4][5][6][7] Pharmacogenomics is a powerful tool to identify different individual metabolism patterns, 8 yet this method only d...

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Mechanisms of Acetaminophen-Induced Liver Necrosis

Cited by 862 publications

References 203 publications

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Attenuation of copaiba oil in hepatic damage in rats

Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies

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