Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Yohe, Herbert C.; O’Hara, Kimberley A.; Hunt, Jane; Kitzmiller, Tamar J.; Wood, Sheryl G.; Bement, Jenna; Bement, William J.; Szakacs, Juliana G.; Wrighton, Steven; Jacobs, Judith M.; Kostrubsky, Vsevolod E.; Sinclair, Peter R.; Sinclair, Jacqueline F.

doi:10.1152/ajpgi.00239.2005

Cited by 64 publications

(48 citation statements)

References 67 publications

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“…It is noteworthy that APAP intoxication in wild-type mice induced macrovacuolar steatosis in some hepatocytes (Fig. 2C), as described previously in humans and mice (Yohe et al, 2006;Begriche et al, 2011). Moreover, APAP intoxication aggravated steatosis in obese mice, in particular in ob/ob mice (Fig.…”

Section: Preliminary Investigations In Lean and Obese Micesupporting

confidence: 84%

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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Section: Preliminary Investigations In Lean and Obese Micesupporting

confidence: 84%

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Aubert

Begriche

Delannoy

et al. 2012

J Pharmacol Exp Ther

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“…-/-mice are resistant to APAP toxicity (50). The modeling and prediction of human variability in DILI in animal models remains a major goal for safe drug development.…”

Section: O V E M B E R -D E C E M B E R 2 0 1 0 F a S T I N G I N H Imentioning

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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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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“…Activation of TLR4 can cause liver injury in several pathological processes such as hemorrhagic shock, hepatic ischemia/ reperfusion injury, alcohol-induced liver injury and hepatic failure. [33][34][35][36][37] Inhibition of TLR4 with a TLR4 antagonist or recombinant soluble forms of extracellular TLR4 domain and MD-2 can attenuate myocardial ischemia-reperfusion injury, dampen lipopolysaccharide-induced pulmonary inflammation in mice and have anti-inflammatory effects in murine models of inflammatory bowel disease. [38][39][40] Our finding of elevated expression of TLR4 in hepatocytes may have a role in the pathogenesis of CHB while little effect on the inhibition of replication of HBV, TLR4 antagonist may be helpful in the treatment of CHB.…”

Section: Discussionmentioning

confidence: 99%

The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B

Wei¹,

Guo²,

Liu³

et al. 2008

CIM

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Results: TLR4 expressed mainly in the cytoplasm and some on cell membrane in hepatocytes. The staining scores of TLR4 expression in the liver tissues of patients with CHB were significantly higher than that of healthy controls. The liver tissues from patients with severe CHB expressed higher level of TLR4 than those from patients with mild CHB. Furthermore, the staining scores of TLR4 expression in the liver tissues of patients with CHB were positively correlated with the grading scores. Our results also showed that the mean fluorescence intensity and TNFsecretion induced by endotoxin as well as the protein and mRNA 1eve1s of TLR4 in HepG2.2.15 cells were all significantly higher than those in HepG2 cells. Conclusion: TLR4 was up-regulated in the hepatocytes in patients with CHB. This indicates a potentially important interaction between TLR4 expression and the pathogenesis of CHB.Mechanisms responsible for chronic hepatitis B remain incompletely understood, although increasing evidence points to immunological rather than direct viral effects playing a central role. 1,2 However, most studies have focused on adaptive immunity, with little research on the innate immunity. One of the key components of the innate immune response is the family of Toll-like receptors(TLRs), evolutionarily conserved pattern recognition receptors. Activation of TLRs triggered by various motifs common to microorganisms, known as pathogen-associated molecular patterns, can promote the inflammatory response, the antiinfectious response and the maturation of antigen pre-ORIGINAL RESEARCH

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Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Cited by 64 publications

References 67 publications

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

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

The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B

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