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Molecular Toxicology of Drug Induced Liver Injury
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Molecular Toxicology of Drug Induced Liver Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 12653

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
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Special Issue Information

Dear Colleagues,

Published reports suggest that some hundreds of drugs may be toxic, causing drug-induced liver injury (DILI), although evidence of a robust causal attribution for all incriminated drugs is not always provided. According to prevailing mainstream concepts, liver injury by drugs is due to overdosed drugs, causing intrinsic injury, or to drugs used in recommended doses, causing idiosyncratic liver injury. Whereas the molecular toxicology of the intrinsic liver injury is largely known from experimental and clinical studies, this does not apply to the idiosyncratic liver injury due to the lack of data reproducibility in animal models. As a result, studies on molecular toxicology are mostly limited to clinical research focusing on patients with idiosyncratic liver injury assessed for causality using preferentially the Roussel Uclaf Causality Assessment Method (RUCAM), a diagnostic algorithm in worldwide use and applied in most national and regional DILI registries like in Spain, Iceland, the Latin American region, and many Asian countries including Japan, China, and Korea. Possible keywords for submissions are diagnostic biomarkers, genetics, immune mechanisms, reactive oxygen species (ROS), cytochrome P450 (CYP), blood exosomes, and risk factors under discussion such as drug lipophilicity, daily dose, and metabolic rate. The aim of this Special Issue is to provide a broad updated overview on these molecule-related liver injury features with their challenges and highlights and to foster more molecular research in DILI. Experts in the field are encouraged to contribute their new results and views to this emerging and fascinating topic of molecular aspects. Since some topics are still controversial, we expect expert submissions and appreciate lively discussions, in addition to well-settled issues that are relevant to the clinical setting of molecular DILI and require balanced statements.

Prof. 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.

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Keywords

  • liver injury
  • drug-induced liver injury (DILI)
  • hepatotoxicity
  • molecular toxicology
  • drug toxicology

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Published Papers (3 papers)

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Research

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64 pages, 31663 KiB  
Article
Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury—A Repeated Dose Study in Minipigs for 28 Days
by Saravanakumar Selvaraj, Jung-Hwa Oh, Seokjoo Yoon and Jürgen Borlak
Int. J. Mol. Sci. 2023, 24(2), 1445; https://doi.org/10.3390/ijms24021445 - 11 Jan 2023
Cited by 4 | Viewed by 3556
Abstract
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an [...] Read more.
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ß-defensin. Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response. Full article
(This article belongs to the Special Issue Molecular Toxicology of Drug Induced Liver Injury)
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23 pages, 3680 KiB  
Article
Effect of Pd2Spermine on Mice Brain-Liver Axis Metabolism Assessed by NMR Metabolomics
by Tatiana J. Carneiro, Martin Vojtek, Salomé Gonçalves-Monteiro, Ana L. M. Batista de Carvalho, Maria Paula M. Marques, Carmen Diniz and Ana M. Gil
Int. J. Mol. Sci. 2022, 23(22), 13773; https://doi.org/10.3390/ijms232213773 - 9 Nov 2022
Cited by 1 | Viewed by 2499
Abstract
Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance [...] Read more.
Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd2Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd2Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd2Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd2Spm as a promising replacement of cDDP. Full article
(This article belongs to the Special Issue Molecular Toxicology of Drug Induced Liver Injury)
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Review

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15 pages, 326 KiB  
Review
Hepatotoxicity of Drugs Used in Multiple Sclerosis, Diagnostic Challenge, and the Role of HLA Genotype Susceptibility
by Lucy Meunier and Dominique Larrey
Int. J. Mol. Sci. 2023, 24(1), 852; https://doi.org/10.3390/ijms24010852 - 3 Jan 2023
Cited by 6 | Viewed by 5920
Abstract
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and the association with other autoimmune diseases is well-documented. There are many therapeutic options for the treatment of MS. Most of the available drugs cause drug-induced liver injury (DILI) to [...] Read more.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and the association with other autoimmune diseases is well-documented. There are many therapeutic options for the treatment of MS. Most of the available drugs cause drug-induced liver injury (DILI) to variable extents with heterogeneous clinical and biological manifestations, including liver injury with or without signs of hypersensitivity and autoimmunity. The diagnosis of DILI may be particularly difficult because MS is frequently associated with idiopathic autoimmune hepatitis. Recent advances suggest that MS and immune-mediated DILI could be promoted by genetic factors, including HLA genotype. In addition, some of these drugs may promote hepatitis B virus reactivation. This review explores the potential hepatotoxicity of drugs used to treat MS and the criteria to distinguish DILI from idiopathic autoimmune hepatitis associated with MS. The role of susceptible genes both promoting MS and causing the hepatotoxicity of the drug used for MS treatment is also discussed. Full article
(This article belongs to the Special Issue Molecular Toxicology of Drug Induced Liver Injury)
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