Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related hepatotoxicity

Myers, Robert P.; Shaheen, Muzaffar

doi:10.1002/hep.22798

Cited by 29 publications

(29 citation statements)

References 12 publications

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“…In conclusion, we set up a cellular model of human NAFLD which can be a valuable tool to gain insight regarding the mechanisms whereby this frequent hepatic disease appears to favor APAP-induced acute liver failure in some patients, in particular after an overdose (Michaut et al, 2014; Myers and Shaheen, 2009; NGuyen et al, 2008). This model can also be used to test the effect of other drugs or toxins suspected to be more hepatotoxic in the context of obesity and NAFLD, especially as a consequence of CYP2E1 induction (Fromenty, 2013).…”

Section: Discussionmentioning

confidence: 99%

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

Michaut

Guillou

Moreau

et al. 2016

Toxicology and Applied Pharmacology

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Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

Michaut

Guillou

Moreau

et al. 2016

Toxicology and Applied Pharmacology

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“…Results from both clinical human and experimental animal studies generally suggests that NAFLD may promote APAP‐induced liver injury although some conflicting observations also exist . Several clinical studies revealed that NAFLD patients may have a higher risk of APAP‐induced hepatotoxicity but not obesity itself . However, experimental evidence from rodents yields mixed conclusions.…”

Section: Autophagy and Nonalcoholic Fatty Liver Disease In Apap Hepatmentioning

confidence: 99%

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Chao

Wang

Jaeschke

et al. 2018

Liver International

117

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Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury.

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“…The possible effect of viral infections on drug metabolism has been recognized for decades (104, 105) and recent epidemiological data indicate that hepatitis C virus (HCV) infection predisposes patients to APAP‐induced acute liver injury (106, 107). Viral infections result in elevated levels of type I IFNs (108) and the IFN inducer poly rI:rC has been used in a number of studies evaluating immune modulation of APAP toxicity.…”

Section: Bacterial and Viral Infections And Acetaminophen Toxicitymentioning

confidence: 99%

Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity

Jaeschke

Williams

Ramachandran

et al. 2011

Liver International

414

368

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Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair.

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Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related hepatotoxicity

Cited by 29 publications

References 12 publications

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity

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