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Biomedicines
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Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches
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Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 17855

Special Issue Editor

Dr. Sanda Win

E-Mail Website
Guest Editor
Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
Interests: signal transduction in drug-induced hepatotoxicity; regulation of mitochondrial bioenergetic signaling in hepatotoxicity; metabolic dysfunction-associated steatotic liver disease (MASLD); alcoholic hepatitis; identification of therapeutic targets; cellular mechanisms of hepatotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease. DILI is caused specifically by medications (drugs/herbal), chemical agents, and dietary supplements, and most DILIs improve after drug withdrawal.

The liver is the main organ for metabolized and detoxification chemicals and is susceptible to the toxicity of these agents. Drugs associated with DILIs may cause injury in a dose-dependent, predictable hepatotoxicity (e.g., acetaminophen) or in an unpredictable (idiosyncratic) hepatotoxicity in susceptible individuals. Most idiosyncratic drug reactions are caused by immune-mediated toxicity. Idiosyncratic DILI is mainly mediated by the innate or adaptive immune response, involving death ligands such as TNFα and FasL. TNF-α and FasL bind to death receptors of hepatocytes, triggering apoptotic cell death.

Drugs or their toxic metabolites cause the activation of MAP kinases or deactivation of signaling pathways. Then, it causes the impairment of mitochondrial function, oxidative stress, mitochondria damaged, and hepatocyte death.

Moreover, the endogenous defense system of the liver is made up of endogenous nonprotein antioxidants and endogenous protein antioxidants. The main endogenous antioxidants are glutathione, lipoic acid, bilirubin, ferritin, superoxide dismutase, catalase, and glutathione peroxidase. Their main function is to maintain redox homeostasis in the liver.

The aim of this Special Issue on Drug-Induced Hepatotoxicity is to discuss updated recent findings in mechanisms of drug induced hepatoxicity and potential therapeutic targets. Original articles and review articles on the following topics are welcome.

Dr. Sanda Win
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • cell death
  • reactive metabolites
  • oxidative stress
  • stress signaling
  • mitochondria
  • adaptive immunity
  • HLA associations
  • hepatotoxicity
  • drugs
  • liver injury
  • adverse drug reaction
  • drug-induced autoimmune hepatitis
  • idiosyncratic drug-induced liver injury
  • bile acid
  • drug-induced cholestasis

Published Papers (5 papers)

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Research

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15 pages, 2134 KiB  
Article
Differential iNKT and T Cells Activation in Non-Alcoholic Fatty Liver Disease and Drug-Induced Liver Injury
by Estefanía Caballano-Infantes, Alberto García-García, Carlos Lopez-Gomez, Alejandro Cueto, Mercedes Robles-Diaz, Aida Ortega-Alonso, Flores Martín-Reyes, Ismael Alvarez-Alvarez, Isabel Arranz-Salas, Francisco Ruiz-Cabello, Isabel M. Lucena, Eduardo García-Fuentes, Raúl J. Andrade and Miren García-Cortes
Biomedicines 2022, 10(1), 55; https://doi.org/10.3390/biomedicines10010055 - 28 Dec 2021
Cited by 5 | Viewed by 2252
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI. Methods: We [...] Read more.
Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI. Methods: We analyzed the activation profile (CD69, CD25, and HLA-DR) and natural killer group 2 member D (NKG2D) on iNKT cells, and CD4/CD8 T cells in peripheral blood mononuclear cells from NAFLD, with or without significant liver fibrosis, and DILI patients. Results: There was an increase in iNKT cells in NAFLD patients compared to DILI or control subjects. Regarding the cellular activation profile, NAFLD with significant liver fibrosis (F ≥ 2) displayed higher levels of CD69+iNKT cells compared to NAFLD with none or mild liver fibrosis (F ≤ 1) and control patients. CD69+iNKT positively correlated with insulin resistance, aspartate aminotransferase (AST) level, liver fibrosis-4 index (FIB4) and AST to Platelet Ratio Index (APRI). DILI patients showed an increase in CD69+ and HLA-DR+ in both CD4+ and CD8+ T cells, detecting the most relevant difference in the case of CD69+CD8+ T cells. Conclusions: CD69+iNKT may be a biomarker to assess liver fibrosis progression in NAFLD. CD69+CD8+ T cells were identified as a potential distinctive biomarker for distinguishing DILI from NAFLD. Full article
(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)
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17 pages, 3922 KiB  
Article
Enhancement of TEX264-Mediated ER-Phagy Contributes to the Therapeutic Effect of Glycycoumarin against APA Hepatotoxicity in Mice
by Mingzhu Yan, Zhi Wang, Tianji Xia, Suwei Jin, Yongguang Liu, Hongbo Hu and Qi Chang
Biomedicines 2021, 9(8), 939; https://doi.org/10.3390/biomedicines9080939 - 2 Aug 2021
Cited by 5 | Viewed by 2346
Abstract
Acetaminophen (APA)-induced hepatotoxicity is coupled with the activation of autophagy. We sought to determine whether selective autophagy of the endoplasmic reticulum (ER), termed ER-phagy, is involved in APA hepatotoxicity and to explore its potential as a therapeutic target for APA-induced liver injury (AILI). [...] Read more.
Acetaminophen (APA)-induced hepatotoxicity is coupled with the activation of autophagy. We sought to determine whether selective autophagy of the endoplasmic reticulum (ER), termed ER-phagy, is involved in APA hepatotoxicity and to explore its potential as a therapeutic target for APA-induced liver injury (AILI). APA (300 or 600 mg/kg) was administered to male C57BL/6N mice, with and without rapamycin, glycycoumarin (GCM) and N-acetylcysteine (NAC). The results demonstrated that ER-phagy accompanied with ER stress was activated after APA overdose. The dynamic changes of LC3 and TEX264 revealed that ER-phagy was induced as early as 6 h and peaked at 24 h following the APA injection. A delayed treatment with GCM, but not rapamycin, considerably attenuated a liver injury and, consequently, reduced its mortality. This is probably due to the inhibition of ER stress and the acceleration of liver regeneration via enhanced ER-phagy. Unlike the impaired hepatocyte proliferation and more severe liver injury in mice that received prolonged treatment with NAC, liver recovery is facilitated by repeated treatment with GCM. These findings suggest that TEX264-mediated ER-phagy is a compensatory mechanism against ER stress provoked by an APA overdose. A delayed and prolonged treatment with GCM enhances ER-phagy, thus serving as a potential therapeutic approach for patients presenting at the late stage of AILI. Full article
(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)
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Review

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16 pages, 990 KiB  
Review
Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease
by Robert W. M. Min, Filbert W. M. Aung, Bryant Liu, Aliza Arya and Sanda Win
Biomedicines 2022, 10(8), 2035; https://doi.org/10.3390/biomedicines10082035 - 20 Aug 2022
Cited by 11 | Viewed by 2433
Abstract
Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially [...] Read more.
Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease. Full article
(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)
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25 pages, 17474 KiB  
Review
Probiotics: Evolving as a Potential Therapeutic Option against Acetaminophen-Induced Hepatotoxicity
by Saikat Dewanjee, Tarun K. Dua, Paramita Paul, Abhijit Dey, Jayalakshmi Vallamkondu, Sonalinandini Samanta, Ramesh Kandimalla and Vincenzo De Feo
Biomedicines 2022, 10(7), 1498; https://doi.org/10.3390/biomedicines10071498 - 24 Jun 2022
Cited by 7 | Viewed by 3255
Abstract
Acetaminophen (APAP) is the most common prescription medicine around the world for the treatment of pain and fever and is considered to be a safe drug at its therapeutic dose. However, a single overdose or frequent use of APAP can cause severe acute [...] Read more.
Acetaminophen (APAP) is the most common prescription medicine around the world for the treatment of pain and fever and is considered to be a safe drug at its therapeutic dose. However, a single overdose or frequent use of APAP can cause severe acute liver injury. APAP hepatotoxicity is a prevalent cause of acute liver disease around the world and the lack of suitable treatment makes it a serious problem. In recent years, there has been a surge in interest in using probiotics and probiotic-derived products, known as postbiotics, as health and disease negotiators. A growing body of evidence revealed that they can be equally effective against APAP hepatotoxicity. Different probiotic bacteria were found to be pre-clinically effective against APAP hepatotoxicity. Different postbiotics have also shown exciting results in preclinical models of APAP hepatotoxicity. This review summarized the protective roles and mechanisms of the different probiotic bacteria and postbiotics against APAP hepatotoxicity, with critical discussion. A brief discussion on potential novel probiotics and postbiotics for oxidative liver injury was also included. This review was written in an attempt to pique the interest of researchers in developing a safe therapeutic option against oxidative liver damage using probiotics and/or postbiotics as dietary supplements. Full article
(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)
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33 pages, 2269 KiB  
Review
Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update
by Laura Giuseppina Di Pasqua, Marta Cagna, Clarissa Berardo, Mariapia Vairetti and Andrea Ferrigno
Biomedicines 2022, 10(1), 194; https://doi.org/10.3390/biomedicines10010194 - 17 Jan 2022
Cited by 10 | Viewed by 6517
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search. Full article
(This article belongs to the Special Issue Drug-Induced Hepatotoxicity: From Pathology to Novel Therapeutic Approaches)
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