Susceptibility of rat non‐alcoholic fatty liver to the acute toxic effect of acetaminophen

Kučera, Otto; Roušar, Tomáš; Staňková, Pavla; Haňáčková, Lenka; Lotková, Halka; Podhola, Miroslav; Červinková, Z

doi:10.1111/j.1440-1746.2011.06807.x

Cited by 31 publications

(25 citation statements)

References 51 publications

(87 reference statements)

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“…55 However, the contribution of this enzyme to GSH depletion and liver injury in paracetamol intoxication remains controversial. 13 in the present study, a significant increase in the GSH level in the liver was found 190 MLADENOVIĆ et al 24 h after paracetamol administration in comparison with the control group. 56 Although π class GST was found at high levels in mice liver, mGstp1/2-/-mice (knockout mice for π-GST gene) challenged with an overdose of paracetamol exhibited a markedly decreased, not increased hepatotoxicity when compared to mGstp1/2+/+ mice.…”

Section: Discussionsupporting

confidence: 57%

“…The liver GSH content was significantly lower in ethanol-and paracetamoltreated groups (0.58±0.05 and 0.75±0.06 nmol mg -1 protein, respectively) in comparison with control group (1.03±0.12 nmol mg -1 protein) 6 h after treatment (p < 0.01), Fig. Prior ethanol administration did not significantly potentiate the paracetamol-induced decrease in SOD activity within the first 24 In contrast to the total SOD activity, the mitochondrial SOD activity was higher after 6 h in all treated groups in comparison with the control group (Fig. Within the next 18 h, its content returned to the control range in the ethanol-treated group (0.99±0.09 nmol mg -1 protein) and remained approximately constant within the next 24 h (1.05±0.11 nmol mg -1 protein) (p > > 0.05).…”

Section: Resultsmentioning

confidence: 74%

“…The study also showed that the serum MDA concentration was significantly higher in all groups that received either ethanol or paracetamol at all times when blood samples were collected (Table I). For statistical evaluation, multifactorial ANOVA with Tukey's post hoc test were used (*p < 0.05, **p < 0.01 vs. the control group, # p < 0.05, ## p < 0.01 in comparison with the group on the same experimental protocol 6 (a) and 24 h (b) after treatment); abbreviations: C 6 , C 24 , C 48 , control group 6, 24 and 48 h after treatment; P 6 , P 24 The liver NO x concentration was significantly higher in the paracetamoltreated group (1.24±0.41 μmol L -1 ) than in the control group (0.34±0.06 μmol L -1 ) 6 h after treatment (p < 0.01) (Fig. A similar increase was found after ethanol administration (4.78±0.69 μmol L -1 ) (p < 0.01).…”

Section: Resultsmentioning

confidence: 99%

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The effects of ethanol on paracetamol-induced oxidative stress in mice liver

Mladenović¹,

Ninković²,

Vučević³

et al. 2013

JSCS

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The aim of our study was to investigate the effects of binge drinking on paracetamol induced oxidative stress in mice liver. Male Swiss mice were divided into groups: control; ethanol-treated group (E) in five subsequent doses of 2 g/kg by orogastric tube; paracetamol-treated group (P) in a dose of 300 mg/kg intraperitoneally; group that received paracetamol 12 hrs after the last dose of ethanol (PE). Blood and liver samples were collected for determination of oxidative stress parameters 6, 24 and 48 hrs after treatment. Prior binge drinking potentiated paracetamol-induced rise in liver malondialdehyde level 48 hours after treatment in comparison with P and E groups (17.14 ± 1.98 vs 13.14 ± 0.82 and 12.99 ± 1.18 μmol/L, p<0.01). Ethanol and paracetamol in combination induced a more pronounced decrease in liver GSH level than either of these substances alone at all time intervals (p<0.01). Total liver superoxide dismutase (SOD) activity was significantly lower in PE 48 hours after treatment in comparison with P and E groups (251.73 ± 80.63 vs 707.62 ± 179.92 and 1179.62 ± 147.94 U/mg prot., p<0.01). The lowest MnSOD activity in PE group was detected 48 hrs after treatment (86.52 ± 28.31; 41.13 ± 11.07 and 23.16 ± 5.18 U/mg prot. in P, E and PE groups, p<0.05, respectively). Prior binge ethanol drinking potentiates paracetamol-induced reduction of antioxidative capacity of hepatocytes due to GSH depletion and SOD activity reduction, simultaneously increasing lipid peroxidation caused by paracetamol. [Projekat Ministarstva nauke Republike Srbije, br. 175015

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Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The effects of ethanol on paracetamol-induced oxidative stress in mice liver

Mladenović¹,

Ninković²,

Vučević³

et al. 2013

JSCS

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“…However, these investigations have shown conflicting results. Indeed, whereas some studies showed increased hepatotoxicity (Corcoran and Wong, 1987;Kon et al, 2010;Kučera et al, 2012), others demonstrated no difference or an obvious protection (Blouin et al, 1987;Ito et al, 2006;Sawant et al, 2006). Although the exact reasons for this discrepancy are currently unknown, several hypotheses can be put forward.…”

Section: Introductionmentioning

confidence: 99%

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Aubert

Begriche

Delannoy

et al. 2012

J Pharmacol Exp Ther

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Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The preexistence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and ␤-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.

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“…This susceptibility, also found in trib1 morphants, might be APAP specific, but might also be correlated to plasma liver enzyme elevation. For example, liver enzymes increase not only during APAP-induced liver toxicity but also in other types of metabolic or toxic liver injury, and enzyme levels can be further increased by APAP exposure (Aubert et al, 2012; Kučera et al, 2012; Majhi et al, 2011). These functional data might inform further genomic studies to identify differentiating SNPs between pnpla3 and samm50 that could correlate with gene function.…”

Section: Discussionmentioning

confidence: 99%

Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development

Liu

Fox

North

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYGenome-wide association studies (GWAS) have revealed numerous associations between many phenotypes and gene candidates. Frequently, however, further elucidation of gene function has not been achieved. A recent GWAS identified 69 candidate genes associated with elevated liver enzyme concentrations, which are clinical markers of liver disease. To investigate the role of these genes in liver homeostasis, we narrowed down this list to 12 genes based on zebrafish orthology, zebrafish liver expression and disease correlation. To assess the function of gene candidates during liver development, we assayed hepatic progenitors at 48 hours post fertilization (hpf) and hepatocytes at 72 hpf using in situ hybridization following morpholino knockdown in zebrafish embryos. Knockdown of three genes (pnpla3, pklr and mapk10) decreased expression of hepatic progenitor cells, whereas knockdown of eight genes (pnpla3, cpn1, trib1, fads2, slc2a2, pklr, mapk10 and samm50) decreased cell-specific hepatocyte expression. We then induced liver injury in zebrafish embryos using acetaminophen exposure and observed changes in liver toxicity incidence in morphants. Prioritization of GWAS candidates and morpholino knockdown expedites the study of newly identified genes impacting liver development and represents a feasible method for initial assessment of candidate genes to instruct further mechanistic analyses. Our analysis can be extended to GWAS for additional disease-associated phenotypes.

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Susceptibility of rat non‐alcoholic fatty liver to the acute toxic effect of acetaminophen

Abstract: Liver from rats fed HFGD is more susceptible to acute toxic effect of acetaminophen, compared to non-steatotic liver.

Cited by 31 publications

References 51 publications

The effects of ethanol on paracetamol-induced oxidative stress in mice liver

The effects of ethanol on paracetamol-induced oxidative stress in mice liver

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development

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