Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

High doses of acetaminophen (APAP;N-acetyl-p-aminophenol) cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg). Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

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Faculty Opinions recommendation of Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717955250.793460400 ◽

2012 ◽

Author(s):

Ralf Weiskirchen

Keyword(s):

Gap Junction ◽

Fulminant Hepatic Failure ◽

Hepatic Failure ◽

Liver Toxicity ◽

Drug Induced ◽

Gap Junction Inhibition

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

Nature Biotechnology ◽

10.1038/nbt.2089 ◽

2012 ◽

Vol 30 (2) ◽

pp. 179-183 ◽

Cited By ~ 78

Author(s):

Suraj J Patel ◽

Jack M Milwid ◽

Kevin R King ◽

Stefan Bohr ◽

Arvin Iracheta-Vellve ◽

...

Keyword(s):

Gap Junction ◽

Fulminant Hepatic Failure ◽

Hepatic Failure ◽

Liver Toxicity ◽

Drug Induced ◽

Gap Junction Inhibition

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RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

10.1101/357582 ◽

2018 ◽

Author(s):

Tomoyoshi Inoue ◽

Yoshiya Ito ◽

Nobuyuki Nishizawa ◽

Koji Eshima ◽

Ken Kojo ◽

...

Keyword(s):

T Cells ◽

Liver Injury ◽

Kupffer Cells ◽

Immune Cells ◽

Critical Role ◽

Dependent Manner ◽

Immune Mediated ◽

A Subunit ◽

Sensory Nervous System ◽

Deficient Mice

AbstractThe significanceF of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.

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Paradoxical Role of Matrix Metalloproteinases in Liver Injury and Regeneration after Sterile Acute Hepatic Failure

Cells ◽

10.3390/cells7120247 ◽

2018 ◽

Vol 7 (12) ◽

pp. 247 ◽

Cited By ~ 5

Author(s):

Débora Alvarenga ◽

Matheus Mattos ◽

Mateus Lopes ◽

Sarah Marchesi ◽

Alan Araújo ◽

...

Keyword(s):

Liver Injury ◽

Matrix Metalloproteinases ◽

Hepatic Failure ◽

Acute Hepatic Failure ◽

Neutrophil Infiltration ◽

Hepatic Necrosis ◽

Pharmacological Intervention ◽

Neutrophil Accumulation ◽

Drug Induced

Acetaminophen (APAP) poisoning is one of the leading causes of acute hepatic failure and liver transplantation is often the only lifesaving alternative. During the course of hepatocyte necrosis, an intense accumulation of neutrophils is often observed within the liver microenvironment. Despite the classic idea that neutrophil accumulation in tissues causes collateral tissue damage, there is a growing body of evidence showing that neutrophils can also orchestrate the resolution of inflammation. In this work, drug-induced liver injury was induced by oral administration of APAP and pharmacological intervention was made 12 h after this challenge. Liver injury and repair kinetics were evaluated by a novel combination of enzyme quantifications, ELISA, specific antagonists of neutrophil enzymes and confocal intravital microscopy. We have demonstrated that neutrophil infiltration is not only involved in injury amplification, but also in liver tissue repair after APAP-induced liver injury. In fact, while neutrophil depletion led to reduced hepatic necrosis during APAP poisoning, injury recovery was also delayed in neutropenic mice. The mechanisms underlying the neutrophil reparative role involved rapid degranulation and matrix metalloproteinases (MMPs) activity. Our data highlights the crucial role of neutrophils, in particular for MMPs, in the resolution phase of APAP-induced inflammatory response.

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

Nature Biotechnology ◽

10.1038/nbt0314-291c ◽

2014 ◽

Vol 32 (3) ◽

pp. 291-291 ◽

Cited By ~ 1

Author(s):

Suraj J Patel ◽

Jack M Milwid ◽

Kevin R King ◽

Stefan Bohr ◽

Arvin Iracheta-Velle ◽

...

Keyword(s):

Gap Junction ◽

Fulminant Hepatic Failure ◽

Hepatic Failure ◽

Liver Toxicity ◽

Drug Induced ◽

Gap Junction Inhibition

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The effect of acute hepatic failure on drug handling in the critically ill

10.1093/med/9780199600830.003.0197 ◽

2016 ◽

Author(s):

Andreas Kortgen ◽

Michael Bauer

Keyword(s):

Hepatic Failure ◽

Protein Function ◽

Acute Hepatic Failure ◽

Hepatic Function ◽

Therapeutic Drug ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Transporter Protein ◽

Underlying Mechanisms ◽

Drug Handling

Impaired hepatic function is a common event in intensive care unit patients and as the liver plays a central role in drug metabolism and excretion this may lead to profound changes in pharmacokinetics. Underlying mechanisms are altered enzyme function of phase I and phase II metabolism, altered transporter protein function together with cholestasis and hepatic perfusion disorders. Moreover, multidrug therapy may lead to induction and inhibition of these enzymes and transporter proteins. In addition, changes in plasma protein binding and volumes of distribution of drugs are common. Altogether, these changes may not only lead to sometimes unpredictable plasma levels of xenobiotics, but also to drug-induced liver injury when hepatocellular accumulation of noxious substances occurs. Concomitant renal dysfunction may further complicate this situation. Pharmacodynamic alterations might also occur. In conclusion, the clinician must carefully evaluate medication given to patients with hepatic failure. Therapeutic drug monitoring should be performed wherever available to guide therapy.

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