Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury

El-Hassan, Hasan.; Anwar, Khurshid; Macanas-Pirard, Patricia; Crabtree, Mark J.; Chow, Sek C.; Johnson, Victoria L.; Lee, Pauline C.; Hinton, Richard H.; Price, Shirley C.; Kass, George E.N.

doi:10.1016/s0041-008x(03)00240-0

Cited by 140 publications

(133 citation statements)

References 74 publications

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“…Conflicting data exist within the literature regarding the occurrence and consequences of APAP-induced hepatocyte apoptosis during overdose in vivo (7,8). Apoptosis and necrosis frequently coexist in pathological conditions of the liver, and the balance of cell death may be dictated by the particular insult.…”

Section: Introductionmentioning

confidence: 99%

“…Apoptosis and necrosis frequently coexist in pathological conditions of the liver, and the balance of cell death may be dictated by the particular insult. In general, reported investigations that found that apoptosis was not a feature of APAP-induced hepatotoxicity tend to use fasted animal models (6)(7)(8)(9)(10). It is plausible that depletion of hepatic ATP, necessary for the induction of caspase activation, cleavage of caspase substrates and execution of apoptosis, could be a consequence of fasting animals before treatment (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP . We also investigated in fasted mice the critical role played by inhibition of caspasedependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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“…Some reports indicate apoptosis via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and DNA laddering after exposure of mice and mouse hepatocytes to acetaminophen. 19,20 Other studies indicate that the percentage of apoptosis is low in acetaminophen-induced liver injury and that necrosis is the principal mechanism of acetaminophen-induced liver cell death. 21 Because the MPT can initiate both necrotic and apoptotic cell killing, we investigated its role in acetaminophen-induced cytotoxicity of cultured hepatocytes.…”

mentioning

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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“…Apoptosis-related factors such as Bcl-2, 16) Bax, 17) and apoptosis-inducing factor (AIF) 18) and autophagy-related factors such as Atg7 19) and beclin-1 20) have been shown to play a role in APAP hepatotoxicity. Oxidative stress-related factors such as catalase, superoxide dismutase, 21) heme oxygenase-1 (HO-1), 22) and c-jun-N-terminal kinase (JNK) 23) have been shown to mediate pathways critical to the induction of APAP hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR

Kanno

Tomizawa

Yomogida

2016

Biological & Pharmaceutical Bulletin

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Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Drug-induced liver injury from agents such as APAP is known to vary between individuals within a species. To avoid liver injury and ensure the proper use of pharmaceutical products, it is important to be able to predict such risks using genetic information. This study evaluated the use of quantitative real-time polymerase chain reaction (RT-qPCR) to identify mRNAs (carried in the blood of male ddY mice) capable of predicting susceptibility to APAPinduced hepatotoxicity. Screening was performed on samples obtained at 18 h after treatment from mice that had been orally treated with 500 mg/kg APAP. APAP-induced hepatotoxicity was seen in 60% of the mice, and the mortality rate was 12%. Blood APAP concentration did not differ significantly between mice with and without APAP-induced hepatotoxicity. We compared blood mRNA expression levels between mice with (positive, serious or lethal injury) and without hepatotoxicity in the APAP-treated group. The transcript levels of interleukin-encoding loci Il1β, Il10, and tumor necrosis factor (Tnf ) were increased in the lethal injury group. Transcripts of the loci encoding transthyretin (Ttr) and metallothionein 1 (Mt1) showed increases in the liver injury group, while those of the glutathione peroxidase 3-encoding locus (Gpx3) were decreased. APAP hepatotoxicity was potentiated in fasted animals, although fasting did not appear to affect the level of expression of these genes. These results indicate that mRNA expression of Il1β, Il10, Tnf, Ttr, Mt1, and Gpx3 in mouse blood may provide useful surrogate markers of APAP-induced hepatotoxicity.

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Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury

Cited by 140 publications

References 74 publications

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

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

Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR

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