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Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges
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Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges

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 (28 February 2021) | Viewed by 38665

Special Issue Editor

Prof. Dr. Rolf Teschke

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Guest Editor
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: Heavy metals; Heavy metal uptake; Heavy metal disposition, Heavy metal homeostasis; Haber Weiss reaction; Fenton reaction; Benefits and risks for human health; Environmental pollution
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Liver injury by potentially toxic exogenous and endogenous compounds represents major molecular, mechanistic, and medical challenges. Among the hepatotoxic exogenous compounds are conventional drugs, herbal drugs including various traditional herbal products and so-called herbal supplements lacking supplementary features in patients with a normal balanced diet, alcoholic beverages, industrial chemicals such as aliphatic halogenated hydrocarbons like carbon tetrachloride, environmental chemicals such as heavy metals, nature-based products, and compounds ingested with some fungi. Endogenous hepatotoxic compounds are found in individuals suffering from hereditary diseases such as hemochromatosis caused by iron overload, Wilson disease due to copper overload, Gaucher disease caused by accumulation of glucocerebroside, hepatic porphyria due to metabolic problems of hem synthesis, and a vast range of other hereditary diseases. Finally, much interest has focused more recently on molecular, mechanistic, and clinical aspects on overweight patients with nonalcoholic fatty liver disease and progression to nonalcoholic steatonecrosis (NASH) and nonalcoholic liver cirrhosis, including rare hepatocellular carcinoma. Submissions to the International Journal of Molecular Sciences with a current IF of 4.5 are welcome with focus on molecular, mechanistic, and medical challenges; discouraged are purely clinical papers. 

Prof. Dr. Rolf Teschke
Guest Editor

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Published Papers (6 papers)

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Research

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19 pages, 3827 KiB  
Article
Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals
by Vânia Vilas-Boas, Eva Gijbels, Kaat Leroy, Alanah Pieters, Audrey Baze, Céline Parmentier and Mathieu Vinken
Int. J. Mol. Sci. 2021, 22(20), 11005; https://doi.org/10.3390/ijms222011005 - 12 Oct 2021
Cited by 8 | Viewed by 3487
Abstract
Drug-induced liver injury, including cholestasis, is an important clinical issue and economic burden for pharmaceutical industry and healthcare systems. However, human-relevant in vitro information on the ability of other types of chemicals to induce cholestatic hepatotoxicity is lacking. This work aimed at investigating [...] Read more.
Drug-induced liver injury, including cholestasis, is an important clinical issue and economic burden for pharmaceutical industry and healthcare systems. However, human-relevant in vitro information on the ability of other types of chemicals to induce cholestatic hepatotoxicity is lacking. This work aimed at investigating the cholestatic potential of non-pharmaceutical chemicals using primary human hepatocytes cultured in 3D spheroids. Spheroid cultures were repeatedly (co-) exposed to drugs (cyclosporine-A, bosentan, macitentan) or non-pharmaceutical chemicals (paraquat, tartrazine, triclosan) and a concentrated mixture of bile acids for 4 weeks. Cell viability (adenosine triphosphate content) was checked every week and used to calculate the cholestatic index, an indicator of cholestatic liability. Microarray analysis was performed at specific time-points to verify the deregulation of genes related to cholestasis, steatosis and fibrosis. Despite the evident inter-donor variability, shorter exposures to cyclosporine-A consistently produced cholestatic index values below 0.80 with transcriptomic data partially supporting its cholestatic burden. Bosentan confirmed to be hepatotoxic, while macitentan was not toxic in the tested concentrations. Prolonged exposure to paraquat suggested fibrotic potential, while triclosan markedly deregulated genes involved in different types of hepatotoxicity. These results support the applicability of primary human hepatocyte spheroids to study hepatotoxicity of non-pharmaceutical chemicals in vitro. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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Review

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20 pages, 8170 KiB  
Review
CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload
by Riina Harjumäki, Chris S. Pridgeon and Magnus Ingelman-Sundberg
Int. J. Mol. Sci. 2021, 22(15), 8221; https://doi.org/10.3390/ijms22158221 - 30 Jul 2021
Cited by 111 | Viewed by 10568
Abstract
CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation [...] Read more.
CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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21 pages, 1547 KiB  
Review
Liver Injury and the Macrophage Issue: Molecular and Mechanistic Facts and Their Clinical Relevance
by Siyer Roohani and Frank Tacke
Int. J. Mol. Sci. 2021, 22(14), 7249; https://doi.org/10.3390/ijms22147249 - 6 Jul 2021
Cited by 35 | Viewed by 7427
Abstract
The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, [...] Read more.
The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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16 pages, 748 KiB  
Review
Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies
by Rolf Teschke and Gaby Danan
Int. J. Mol. Sci. 2021, 22(7), 3441; https://doi.org/10.3390/ijms22073441 - 26 Mar 2021
Cited by 28 | Viewed by 3587
Abstract
Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review [...] Read more.
Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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26 pages, 961 KiB  
Review
Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges
by Alison Jee, Samantha Christine Sernoskie and Jack Uetrecht
Int. J. Mol. Sci. 2021, 22(6), 2954; https://doi.org/10.3390/ijms22062954 - 14 Mar 2021
Cited by 62 | Viewed by 9451
Abstract
Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused [...] Read more.
Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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13 pages, 1202 KiB  
Review
The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease?
by Brendan Le Daré, Pierre-Jean Ferron and Thomas Gicquel
Int. J. Mol. Sci. 2021, 22(4), 2139; https://doi.org/10.3390/ijms22042139 - 21 Feb 2021
Cited by 19 | Viewed by 3319
Abstract
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases—particularly in the liver. Although these alcoholic liver diseases were initially [...] Read more.
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases—particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this “inflammatory shift”. Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways. Full article
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
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