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Hepatotoxicity: Molecular Mechanisms and Pathophysiology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 64755

Special Issue Editor

Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: alcoholic liver disease; alcoholic liver injury; alcohol metabolism; microsomal ethanol-oxidizing system; drug induced liver injury; herb induced liver injury; herbal traditional Chinese medicine (TCM); dietary supplements; causality assessment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A new Special Issue is planned with a focus on hepatotoxicity and its molecular mechanisms and pathophysiology.

Presently, some advances in clinical and experimental hepatotoxicity are well recognized and amply documented in the scientific literature. To extend the views on these topics, we now welcome submissions related specifically to the broad field of molecular research of hepatotoxicity with focus on molecular mechanisms and pathophysiology, which may include papers of clinical aspects with a strong focus on issues of molecular biology. Among the potentially hepatotoxic chemicals and products of interest are: ethanol and other aliphatic alcohols; halogenated hydrocarbons such as carbon tetrachloride; industrial, occupational, or household products including solvents; environmental impurities such as aflatoxin B1 or natural products such as Amanita phalloides; pesticides; products used for agriculture; products of herbal medicines including Traditional Chinese Medicine; dietary supplements; conventional drugs; various other experimental inorganic or synthetic organic substances; just to name a few examples.

Experts in the field will be invited to submit key feature papers, while others are encouraged to submit unsolicited manuscripts of preferentially experimental studies or review articles of high scientific level. Both balanced views as well as lively discussions on controversial issues are welcome. All manuscripts will undergo peer review processing by external reviewers, after initial evaluation by members of the editorial board/team on their suitability.

Dr. Rolf Teschke
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatotoxicity
  • alcoholic liver disease
  • drug and herb induced liver injury
  • drugs
  • herbs
  • dietary supplements
  • occupational toxins
  • halogenated hydrocarbons
  • natural toxins
  • aflatoxin B1

Published Papers (9 papers)

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Editorial

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5 pages, 184 KiB  
Editorial
Hepatotoxicity: Molecular Mechanisms and Pathophysiology
by Rolf Teschke
Int. J. Mol. Sci. 2019, 20(1), 211; https://doi.org/10.3390/ijms20010211 - 08 Jan 2019
Cited by 5 | Viewed by 3495
Abstract
The current Special Issue is devoted to the broad spectrum of hepatotoxicity with its molecular mechanisms and pathophysiology, presented in eight publications [...] Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)

Research

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14 pages, 2303 KiB  
Article
Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation
by Cristina Maria Sena, Maria Augusta Cipriano, Maria Filomena Botelho and Raquel Maria Seiça
Int. J. Mol. Sci. 2018, 19(9), 2706; https://doi.org/10.3390/ijms19092706 - 11 Sep 2018
Cited by 31 | Viewed by 4246
Abstract
Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, [...] Read more.
Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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17 pages, 2320 KiB  
Article
Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen
by Tomáš Zárybnický, Petra Matoušková, Bibiána Lancošová, Zdeněk Šubrt, Lenka Skálová and Iva Boušová
Int. J. Mol. Sci. 2018, 19(6), 1805; https://doi.org/10.3390/ijms19061805 - 19 Jun 2018
Cited by 16 | Viewed by 4353
Abstract
Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was [...] Read more.
Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound) on cell viability and microRNA (miRNA) expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue), while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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12 pages, 2585 KiB  
Article
Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of HLA-Peptide Complex
by Makoto Hirasawa, Katsunobu Hagihara, Koji Abe, Osamu Ando and Noriaki Hirayama
Int. J. Mol. Sci. 2018, 19(6), 1660; https://doi.org/10.3390/ijms19061660 - 04 Jun 2018
Cited by 7 | Viewed by 3953
Abstract
Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 [...] Read more.
Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove. The analyses also showed that binding of nevirapine at the groove will significantly change the inter-helical distances of the groove. An in vitro competitive assay showed that nevirapine (1000 μM) increases the binding of the HA peptide to HLA-DRB1*01:01 in an allele-specific manner. These results indicate that nevirapine might interact directly with the P4 pocket and modifies its structure, which could change the orientation of loaded peptides and the conformation of HLA-DRB1*01:01; these changes could be distinctively recognized by T-cell receptors. Through this molecular mechanism, nevirapine might stimulate the immune system, resulting in hepatic hypersensitivity reactions. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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Review

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29 pages, 1518 KiB  
Review
Molecular Mechanisms Involved in Oxidative Stress-Associated Liver Injury Induced by Chinese Herbal Medicine: An Experimental Evidence-Based Literature Review and Network Pharmacology Study
by Cheng Zhang, Ning Wang, Yu Xu, Hor-Yue Tan, Sha Li and Yibin Feng
Int. J. Mol. Sci. 2018, 19(9), 2745; https://doi.org/10.3390/ijms19092745 - 13 Sep 2018
Cited by 61 | Viewed by 7529
Abstract
Oxidative stress, defined as a disequilibrium between pro-oxidants and antioxidants, can result in histopathological lesions with a broad spectrum, ranging from asymptomatic hepatitis to hepatocellular carcinoma in an orchestrated manner. Although cells are equipped with sophisticated strategies to maintain the redox biology under [...] Read more.
Oxidative stress, defined as a disequilibrium between pro-oxidants and antioxidants, can result in histopathological lesions with a broad spectrum, ranging from asymptomatic hepatitis to hepatocellular carcinoma in an orchestrated manner. Although cells are equipped with sophisticated strategies to maintain the redox biology under normal conditions, the abundance of redox-sensitive xenobiotics, such as medicinal ingredients originated from herbs or animals, can dramatically invoke oxidative stress. Growing evidence has documented that the hepatotoxicity can be triggered by traditional Chinese medicine (TCM) during treating various diseases. Meanwhile, TCM-dependent hepatic disorder represents a strong correlation with oxidative stress, especially the persistent accumulation of intracellular reactive oxygen species. Of note, since TCM-derived compounds with their modulated targets are greatly diversified among themselves, it is complicated to elaborate the potential pathological mechanism. In this regard, data mining approaches, including network pharmacology and bioinformatics enrichment analysis have been utilized to scientifically disclose the underlying pathogenesis. Herein, top 10 principal TCM-modulated targets for oxidative hepatotoxicity including superoxide dismutases (SOD), malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), glutathione peroxidase (GPx), Bax, caspase-3, Bcl-2, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and nitric oxide (NO) have been identified. Furthermore, hepatic metabolic dysregulation may be the predominant pathological mechanism involved in TCM-induced hepatotoxic impairment. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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21 pages, 1031 KiB  
Review
New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis
by Nahum Mendez-Sanchez, Vania Cesar Cruz-Ramon, Oscar Lenin Ramirez-Perez, Jessica P. Hwang, Beatriz Barranco-Fragoso and Jaqueline Cordova-Gallardo
Int. J. Mol. Sci. 2018, 19(7), 2034; https://doi.org/10.3390/ijms19072034 - 13 Jul 2018
Cited by 103 | Viewed by 8694
Abstract
NASH is becoming increasingly common worldwide because of the growing global prevalence of obesity and consequently NAFLD. Unfortunately, the mechanism of progression of NAFLD to NASH and then cirrhosis is not completely understood. Several factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and [...] Read more.
NASH is becoming increasingly common worldwide because of the growing global prevalence of obesity and consequently NAFLD. Unfortunately, the mechanism of progression of NAFLD to NASH and then cirrhosis is not completely understood. Several factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and bile acid (BA) toxicity, have been reported to be associated with NASH progression. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, which is caused by the ectopic accumulation of triglyceride-derived toxic metabolites and the subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. Adipose tissue (AT), especially visceral AT, comprises multiple cell populations that produce adipokines and insulin-like growth factor, plus macrophages and other immune cells that stimulate the development of lipotoxic liver disease. These biomolecules have been recently linked with many digestive diseases and gastrointestinal malignancies such as hepatocellular carcinoma. This made us question what role lipotoxicity has in the natural history of liver fibrosis. Therefore, this review focuses on the close relationship between AT and NASH. A good comprehension of the pathways that are related to dysregulated AT, metabolic dysfunction, and hepatic lipotoxicity will result in the development of prevention strategies and promising therapeutics for patients with NASH. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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17 pages, 1609 KiB  
Review
Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy
by Sathish Kumar Natarajan and Jamal A. Ibdah
Int. J. Mol. Sci. 2018, 19(1), 322; https://doi.org/10.3390/ijms19010322 - 22 Jan 2018
Cited by 33 | Viewed by 12953
Abstract
Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is [...] Read more.
Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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16 pages, 660 KiB  
Review
The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity
by Florian Schueller, Sanchari Roy, Mihael Vucur, Christian Trautwein, Tom Luedde and Christoph Roderburg
Int. J. Mol. Sci. 2018, 19(1), 261; https://doi.org/10.3390/ijms19010261 - 16 Jan 2018
Cited by 89 | Viewed by 8171
Abstract
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and [...] Read more.
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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1382 KiB  
Review
Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450
by Christopher Trent Brewer and Taosheng Chen
Int. J. Mol. Sci. 2017, 18(11), 2353; https://doi.org/10.3390/ijms18112353 - 08 Nov 2017
Cited by 64 | Viewed by 10360
Abstract
Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals [...] Read more.
Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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