Impaired protein adduct removal following repeat administration of subtoxic doses of acetaminophen enhances liver injury in fed mice

Nguyen, Nga; Akakpo, Jephte Y.; Weemhoff, James L.; Ramachandran, Anup; Ding, Wen–Xing; Jaeschke, Hartmut

doi:10.1007/s00204-021-02985-6

Cited by 15 publications

(21 citation statements)

References 33 publications

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“…It is thought that mainly the adducts on mitochondrial proteins are critical for the initiation of the injury after an acute overdose 44 and thus removal of cytosolic protein adducts may be of limited relevance. However, during chronic treatment with even therapeutic doses of APAP, the removal of these cytosolic protein adducts becomes important as any impairment of autophagy leads to accumulation of these adducts and liver injury even in the absence of mitochondrial protein adducts 182 .…”

Section: General Recommendations For Investigating Therapeutic Efficacy and Mechanisms Of Actionmentioning

confidence: 99%

“…Third, it has to be kept in mind that after an acute single overdose, autophagy can only modulate cell death in the peripheral areas of necrosis because in this zone the cellular stress is more moderate and delayed, allowing adaptive removal of damaged mitochondria to have an impact on cell survival 184 . Hence autophagy has a much more profound impact on APAP-induced liver injury after multiple, lower overdoses than after a single severe overdose 182 . Fourth, the standard model of APAP hepatotoxicity, i .…”

Section: General Recommendations For Investigating Therapeutic Efficacy and Mechanisms Of Actionmentioning

confidence: 99%

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Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Jaeschke

Adelusi

Akakpo

et al. 2021

Acta Pharmaceutica Sinica B

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Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.

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Section: General Recommendations For Investigating Therapeutic Efficacy and Mechanisms Of Actionmentioning

confidence: 99%

Section: General Recommendations For Investigating Therapeutic Efficacy and Mechanisms Of Actionmentioning

confidence: 99%

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Jaeschke

Adelusi

Akakpo

et al. 2021

Acta Pharmaceutica Sinica B

Self Cite

View full text Add to dashboard Cite

show abstract

“…Guyen et al, found that the administration of multiple sub-toxic doses (150 mg/kg) of APAP into mice resulted in the accumulation of NAPQI–protein complexes in mitochondria and induced mitochondrial oxidative stress (OS). This process was amplified by the JNK pathway and further led to the opening of mitochondrial permeability transition pores (MPTPs), decreased membrane potential, and inhibited ATP synthesis, finally resulting in mitochondrial dysfunction and liver cell death [ 23 ]. In addition, excessive APAP can also lead to the degradation of lysosomes and the release of Fe 2+ , which is subsequently transferred into mitochondria by the mitochondrial calcium ion transporter, eventually changing the permeability of and depolarizing the mitochondrial membrane and causing mitochondrial dysfunction [ 24 ].…”

Section: Mitochondrial Dysfunction and Chronic Liver Diseasementioning

confidence: 99%

“…[ [17][18][19][20][21][22][23][24][25] Energy metabolism ATP synthesis is decreased. [17,18,22,25] ROS Oxidative stress occurs, GSH is decreased, and ROS is increased.…”

Section: Morphological Structurementioning

confidence: 99%

Mitochondrial Dysfunction and Chronic Liver Disease

Zhao

Qin

et al. 2022

CIMB

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Mitochondria are generally considered the powerhouse of the cell, a small subcellular organelle that produces most of the cellular energy in the form of adenosine triphosphate (ATP). In addition, mitochondria are involved in various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested in different aspects, like increased mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, adenosine triphosphate (ATP) synthesis disorder, abnormal mitophagy, as well as changes in mitochondrial morphology and structure. Mitochondrial dysfunction is related to the occurrence and development of various chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic fatty liver (AFL), and non-alcoholic fatty liver (NAFL). In this review, we summarize and discuss the role and mechanisms of mitochondrial dysfunction in chronic liver disease, focusing on and discussing some of the latest studies on mitochondria and chronic liver disease.

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“…This is concerning because recent data from rodent studies have revealed that the accumulation of these adducted proteins in hepatocytes due to impaired autophagy or multiple dosing contributes to the pathophysiology of APAP hepatotoxicity. (26,27) Glutathione (GSH) is an antioxidant and nucleophile that has a critical function as a scavenger of N-acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP, to prevent it from binding to proteins, and there is evidence that systemic GSH concentrations decrease with increasing age. (28)(29)(30) Thus, to determine if the increase in day-5 adducts and Cmax could be a result of reduced GSH levels in the older cirrhosis group, we tested for correlations between day-5 adducts or Cmax and age.…”

Section: Pk Of Apap In Subjects With Cirrhosis and Noncirrhotic Controlsmentioning

confidence: 99%

Short‐Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis

et al. 2021

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Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed inperson at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of lowdose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis. (Hepatology Communications 2021;0:1-13).A cetaminophen (APAP) is the most commonly used analgesic in the United States and throughout much of the world. However, overdose of APAP causes massive centrilobular hepatocyte necrosis that can lead to acute liver failure (ALF) and death. It is overwhelmingly the most common cause of drug-induced ALF in the United States and similarly developed countries, accounting for at least 45%-65% of all cases (1) and possibly even more that go undiagnosed. (2) Although mortality is generally lower in APAP-induced ALF compared to other etiologies, the large number of cases makes APAP overdose the most common cause of ALF-related deaths as well.

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Impaired protein adduct removal following repeat administration of subtoxic doses of acetaminophen enhances liver injury in fed mice

Cited by 15 publications

References 33 publications

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Mitochondrial Dysfunction and Chronic Liver Disease

Short‐Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis

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