Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice

Meyers, Laraine L.; Beierschmitt, William P.; Khairallah, Edward A.; Cohen, Steven D.

doi:10.1016/0041-008x(88)90040-3

Cited by 199 publications

(139 citation statements)

References 20 publications

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“…27 Loss of ATP can result from mitochondrial dysfunction, 28,29 but might also be a consequence of NADHϩNAD ϩ consumption by PARP-1 induced by DNA damage. We found that application of 800 mg/kg APAP to WT mice led to a significant (P Ͻ .05) decrease of ATP from 0.42 Ϯ 0.13 mol/g (0-hour control) to 0.18 Ϯ 0.05 mol/g after 8 hours (Fig.…”

Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 99%

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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An overdose of acetaminophen (APAP) (N-acetyl-p-aminophenol) leads to hepatocellular necrosis induced by its metabolite N-acetyl-p-benzoquinone-imine, which is generated during the metabolic phase of liver intoxication. It has been reported that DNA damage occurs during the toxic phase; however, the nucleases responsible for this effect are unknown. In this study, we analyzed the participation of the hepatic endonuclease deoxyribonuclease 1 (DNASE1) during APAP-induced hepatotoxicity by employing a Dnase1 knockout (KO) mouse model. Male CD-1 Dnase1 wild-type (WT) (Dnase1 ؉/؉ ) and KO (Dnase1 ؊/؊ ) mice were treated with 2 different doses of APAP. Hepatic histopathology was performed, and biochemical parameters for APAP metabolism and necrosis were investigated, including depletion of glutathione/glutathione-disulfide (GSH؉GSSG), ␤-nicotinamide adenine dinucleotide (NADH؉NAD ؉ ), and adenosine triphosphate (ATP); release of aminotransferases and Dnase1; and occurrence of DNA fragmentation. As expected, an APAP overdose in WT mice led to massive hepatocellular necrosis characterized by the release of aminotransferases and depletion of hepatocellular GSH؉GSSG, NADH؉NAD ؉ , and ATP. These metabolic events were accompanied by extensive DNA degradation. In contrast, Dnase1 KO mice were considerably less affected. In conclusion, whereas the innermost pericentral hepatocytes of both mouse strains underwent necrosis to the same extent independent of DNA damage, the progression of necrosis to more outwardly located cells was dependent on DNA damage and only occurred in WT mice. Dnase1 aggravates APAP-induced liver necrosis. A cetaminophen, a widely used analgesic, is one of the most commonly overdosed pharmaceuticals. 1 Overdose leads to liver necrosis caused by the electrophilic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is generated via oxidation of acetaminophen (APAP) by a microsomal cytochrome P450 containing mixed-function oxidase system. 2 Subsequent detoxication of NAPQI by cellular glutathione leads to depletion of glutathione/glutathione-disulfide (GSHϩGSSG) followed by NAPQI accumulation and induction of necrosis due to protein arylation and severe oxidative stress. 2,3 Nuclear accumulation of Ca 2ϩ and DNA damage have been described to occur during APAPinduced cytotoxicity of murine hepatocytes in vitro and in vivo. 4-6 DNA damage seems to be an important event, because APAP toxicity was prevented by known inhibitors of Ca 2ϩ -dependent endonucleases, including Ca 2ϩ -chelators such as aurintricarboxylic acid, glycol ether diamine tetra-acetic acid, and the Ca 2ϩ -calmodulin antagonist chlorpromazine. 5,7,8 However, the nucleases involved in APAP-induced DNA damage have not yet been identified.Deoxyribonuclease 1 (DNASE1), a Ca 2ϩ /Mg 2ϩ -dependent secreted endonuclease with a pH optimum of approximately 7.5, hydrolyzes double-stranded DNA generating 5Ј-phospho-tri-and/or tetra-oligonucleotides. 9,10 DNASE1 gene expression has been demonstrated in a number of different organs of the urogenital and ...

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Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 99%

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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“…In mouse hepatocytes, acetaminophen inhibits mitochondrial oxidative phosphorylation, resulting in depletion of adenosine triphosphate (ATP). [5][6][7][8][9] Acetaminophen also depletes both cytosolic and mitochondrial GSH, the potent scavenger of reactive oxygen and peroxynitrite species. 10,11 Although mitochondria are sensitive to acetaminophen toxicity, the precise role of mitochondria, if any, in acetaminophen-induced cell death remains unclear.…”

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confidence: 99%

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. After administration of 10 mmol/L acetaminophen, necrotic killing increased to more than 49% and 74%, respectively, after 6 and 16 hours. MPT inhibitors, cyclosporin A (CsA), and NIM811 temporarily decreased necrotic killing after 6 hours to 26%, but cytoprotection was lost after 16 hours. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization approximately 4.5 hours after acetaminophen administration. CsA delayed these changes, indicative of the MPT, to approximately 11 hours after acetaminophen administration. Apoptosis indicated by nuclear changes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase-3 activation also increased after acetaminophen administration. Fructose (20 mmol/L, an adenosine triphosphategenerating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis from 37% to 59% after 16 hours. In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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“…Modulation of mitochondrial bioenergetics can have wide ranging effects on a pathophysiology, and is one of the mechanisms of protection by the APAP antidote N -acetylcysteine (NAC), which, in addition to replenishing glutathione stores, can also support mitochondrial energy metabolism [18]. Formation of NAPQI protein adducts on mitochondrial proteins increases free radical production [19] and decreases mitochondrial respiration in vivo [20]. Recent evidence from both in vitro as well as in vivo experiments also indicates that APAP interferes with the formation of mitochondrial respiratory super complexes via the mitochondrial negative regulator MCJ, which could be the cause of decreased production of ATP and increased generation of ROS [21].…”

Section: Acetaminophen Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice

Cited by 199 publications

References 20 publications

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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