Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure

Patel, Suraj J.; Milwid, Jack M; King, Kevin R.; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; Vitalo, Antonia G.; Parekkadan, Biju; Jindal, Rohit; Yarmush, Martin L.

doi:10.1038/nbt.2089

Cited by 110 publications

(108 citation statements)

References 29 publications

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“…Tissue Scrape-and-Load Assay for Gap Junction Function-A dye solution containing 0.5% (v/v) Lucifer yellow (Invitrogen) and 0.5% (v/v) 10-kDa dextran-Texas Red (Invitrogen) was placed onto the surface of freshly prepared liver tissues, and incisions were made with a scalpel, followed by addition of an excess of dye onto the incisions (1,22). After incubation with the dye for 5 min, liver slices were washed with phosphate-buffered saline and then fixed with 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

Park

Erez-Roman

et al. 2013

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

Park

Erez-Roman

et al. 2013

Journal of Biological Chemistry

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“…Limaye et al (2003) noted that propagation effects continue in liver injury after the toxic compound has cleared the liver and probably are a contributor to lethality. Mehendale and Limaye (2005) implicate calpain as a contributor to this propagation effect; others point out that inflammation (Tukov et al, 2006) or communication through gap junctions (Patel et al, 2012) may play a role in propagation. In our model, the propagation effect is modeled by a steep Hill function that represents a "trigger" determined by the size and duration of the necrotic flux.…”

Section: Nac Treatment Analysis Using a Systems Model Of The Liver 537mentioning

confidence: 99%

An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Woodhead

Howell²,

Yang³

et al. 2012

J Pharmacol Exp Ther

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N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n ϭ 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V max for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

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“…The predominant hepatic gap junction, connexin 32 (Cx32), is widely expressed throughout the liver and is most highly expressed in zone 3, the area most vulnerable to injury from steatohepatitis 10. Multiple prior investigations have demonstrated the critical role of Cx32 gap junctions in establishing injury in various models of liver disease 11, 12, 13. In particular, recent data have highlighted that perturbations in Cx32 are associated with the development of NAFLD in dietary animal models 14, 15, 16, 17…”

mentioning

confidence: 99%

Hepatic connexin 32 associates with nonalcoholic fatty liver disease severity

Luther

Gala

Masia

et al. 2018

Hepatology Communications

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Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet‐induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786‐797)

show abstract

Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure

Cited by 110 publications

References 29 publications

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Hepatic connexin 32 associates with nonalcoholic fatty liver disease severity

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