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Molecular Toxicity of Drugs in Human and Animal Organs

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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 August 2023) | Viewed by 8541

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Special Issue Editor

Prof. Dr. Rolf Teschke

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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,

Drugs are valuable tools to treat patients with various diseases or prevent individuals from potential ailments. However, drug use may be complicated by rare toxicitiy observed in various organs such as the liver, heart, kidneys, bone marrow, lungs, gastrointestinal tract, biliary tract, pancreas, skin, central nervous system, and muscles. In terms of clinical significanc, most important are drug toxicities such as liver injury, cardiotoxicity, nephrotoxicity, toxic dermatitis, neurotoxicity, or toxic rhabdomyolysis, just to name a few. It is obvious that drug toxicity is triggered by drug molecules and their metabolic interactions with molecules of target organs, whereby predispostion of susceptible individuals based on some genetic variability may play a contributory role in some organ toxicities. Studies with animals per se lacking human gene specificites are primarily not suitable to mimic human drug toxicity. Instead, sophisticated technologies focussing on gene-expression data in toxicology models will be required to elucidate mechanistic steps leading to better understanding of drug toxicities and their prediction.

We encourage submissions by experts in the field to provide original papers or in- depth review articles on the subject to be included in the special issue: Molecular Toxicity of Drugs in Human and Animal Organs. Presentations of new data suggesting stimulating hypotheses are preferred and must consider molecular aspects, best in relation to clinical features.

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.

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

molecular human drug toxicity
molecular animal drug toxicity
molecular toxicity
liver injury
cardiotoxicity
nephrotoxicity
toxic dermatitis
neurotoxicity
toxic rhabdomyolysis
gene-expression toxicology models
Zebrafish model
drug screening
pre-clinical in vitro safety assays

Published Papers (6 papers)

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Research

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25 pages, 3750 KiB

Open AccessArticle

Multi-Omics Approaches for Freshness Estimation and Detection of Illicit Conservation Treatments in Sea Bass (Dicentrarchus Labrax): Data Fusion Applications

by Alessandro Benedetto, Elisa Robotti, Masho Hilawie Belay, Arianna Ghignone, Alessia Fabbris, Eleonora Goggi, Simone Cerruti, Marcello Manfredi, Elettra Barberis, Simone Peletto, Alessandra Arillo, Nunzia Giaccio, Maria Angela Masini, Jessica Brandi, Daniela Cecconi, Emilio Marengo and Paola Brizio

Int. J. Mol. Sci. 2024, 25(3), 1509; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031509 - 26 Jan 2024

Viewed by 712

Abstract

Fish freshness consists of complex endogenous and exogenous processes; therefore, the use of a few parameters to unravel illicit practices could be insufficient. Moreover, the development of strategies for the identification of such practices based on additives known to prevent and/or delay fish spoilage is still limited. The paper deals with the identification of the effect played by a Cafodos solution on the conservation state of sea bass at both short-term (3 h) and long-term (24 h). Controls and treated samples were characterized by a multi-omic approach involving proteomics, lipidomics, metabolomics, and metagenomics. Different parts of the fish samples were studied (muscle, skin, eye, and gills) and sampled through a non-invasive procedure based on EVA strips functionalized by ionic exchange resins. Data fusion methods were then applied to build models able to discriminate between controls and treated samples and identify the possible markers of the applied treatment. The approach was effective in the identification of the effect played by Cafodos that proved to be different in the short- and long-term and complex, involving proteins, lipids, and small molecules to a different extent. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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23 pages, 3789 KiB

Open AccessArticle

Comparison of Efavirenz and Doravirine Developmental Toxicity in an Embryo Animal Model

by Daniela Zizioli, Sara Ferretti, Giorgio Tiecco, Luca Mignani, Eugenio Monti, Francesco Castelli, Eugenia Quiros-Roldan and Isabella Zanella

Int. J. Mol. Sci. 2023, 24(14), 11664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411664 - 19 Jul 2023

Viewed by 1105

Abstract

In the past, one of the most widely used non-nucleoside reverse transcriptase inhibitors (NNRTI) in first-line antiretroviral therapy (ART) of HIV infection was efavirenz (EFV), which is already used as a cost-effective treatment in developing countries due to its efficacy, tolerability, and availability. However, EFV also demonstrates several adverse effects, like hepatotoxicity, altered lipid profile, neuropsychological symptoms, and behavioral effects in children after in utero exposure. In 2018, another NNRTI, doravirine (DOR), was approved due to its similar efficacy but better safety profile. Preclinical safety studies demonstrated that DOR is not genotoxic and exhibits no developmental toxicity or effects on fertility in rats. Zebrafish (Danio rerio) embryos have been widely accepted as a vertebrate model for pharmacological and developmental studies. We used zebrafish embryos as an in vivo model to investigate the developmental toxicity of DOR compared to EFV. After exposure of the embryos to the drugs from the gastrula stage up to different developmental stages (30 embryos for each arm, in three independent experiments), we assessed their survival, morphology, hatching rate, apoptosis in the developing head, locomotion behavior, vasculature development, and neutral lipid distribution. Overall, DOR showed a better safety profile than EFV in our model. Therapeutic and supra-therapeutic doses of DOR induced very low mortality [survival rates: 92, 90, 88, 88, and 81% at 1, 5, 10, 25, and 50 μM, respectively, at 24 h post fecundation (hpf), and 88, 85, 88, 89, and 75% at the same doses, respectively, at 48 hpf] and mild morphological alterations compared to EFV exposure also in the sub-therapeutic ranges (survival rates: 80, 77, 69, 63, and 44% at 1, 5, 10, 25, and 50 μM, respectively, at 24 hpf and 72, 70, 63, 52, and 0% at the same doses, respectively, at 48 hpf). Further, DOR only slightly affected the hatching rate at supra-therapeutic doses (97, 98, 96, 87, and 83% at 1, 5, 10, 25, and 50 μM, respectively, at 72 hpf), while EFV already strongly reduced hatching at sub-therapeutic doses (83, 49, 11, 0, and 0% at 1, 5, 10, 25, and 50 μM, respectively, at the same time endpoint). Both DOR at therapeutic doses and most severely EFV at sub-therapeutic doses enhanced apoptosis in the developing head during crucial phases of embryo neurodevelopment and perturbed the locomotor behavior. Furthermore, EFV strongly affected angiogenesis and disturbed neutral lipid homeostasis even at sub-therapeutic doses compared to DOR at therapeutic concentrations. Our findings in zebrafish embryos add further data confirming the higher safety of DOR with respect to EFV regarding embryo development, neurogenesis, angiogenesis, and lipid metabolism. Further studies are needed to explore the molecular mechanisms underlying the better pharmacological safety profile of DOR, and further human studies are required to confirm these results in the zebrafish animal model. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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14 pages, 2549 KiB

Open AccessArticle

The Combined Use of Copper Sulfate and Trichlorfon Exerts Stronger Toxicity on the Liver of Zebrafish

by Jianlu Zhang, Mingzhen Zhu, Qijun Wang and Hui Yang

Int. J. Mol. Sci. 2023, 24(13), 11203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311203 - 07 Jul 2023

Cited by 2 | Viewed by 1172

Abstract

In aquaculture, copper sulphate and trichlorfon are commonly used as disinfectants and insecticide, sometimes in combination. However, improper use can result in biotoxicity and increased ecological risks. The liver plays a crucial role in detoxification, lipid metabolism, nutrient storage, and immune function in fish. Selecting the liver as the main target organ for research helps to gain an in-depth understanding of various aspects of fish physiology, health, and adaptability. In the present study, zebrafish were exposed to Cu (0.5 mg/L) and Tri (0.5 mg/L) alone and in combination for 21 days. The results demonstrate that both Cu and Tri caused hepatocyte structure damage in zebrafish after 21 days of exposure, with the combination showing an even greater toxicity. Additionally, the antioxidant and immune enzyme activities in zebrafish liver were significantly induced on both day 7 and day 21. A transcriptome analysis revealed that Cu and Tri, alone and in combination, impacted various physiological activities differently, including metabolism, growth, and immunity. Overall, Cu and Tri, either individually or in combination, can induce tissue damage by generating oxidative stress in the body, and the longer the exposure duration, the stronger the toxic effects. Moreover, the combined exposure to Cu and Tri exhibits enhanced toxicity. This study provides a theoretical foundation for the combined use of heavy metal disinfectants and other drugs. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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15 pages, 4201 KiB

Open AccessArticle

Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats

by Franccesco P. Boeno, Jay Patel, Ryan N. Montalvo, Stephanie S. Lapierre-Nguyen, Claire M. Schreiber and Ashley J. Smuder

Int. J. Mol. Sci. 2023, 24(12), 10222; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210222 - 16 Jun 2023

Cited by 2 | Viewed by 1575

Abstract

Doxorubicin (DOX) is a highly effective chemotherapy agent prescribed for cancer treatment. However, the clinical use of DOX is limited due to off-target toxicity in healthy tissues. In this regard, hepatic and renal metabolic clearance results in DOX accumulation within these organ systems. Within the liver and kidneys, DOX causes inflammation and oxidative stress, which promotes cytotoxic cellular signaling. While there is currently no standard of care to treat DOX hepatic- and nephrotoxicity, endurance exercise preconditioning may be an effective intervention to prevent elevations in liver alanine transaminase (ALT) and aspartate aminotransferase (AST) and to improve kidney creatinine clearance. To determine whether exercise preconditioning is sufficient to reduce liver and kidney toxicity resulting from acute exposure to DOX chemotherapy treatment, male and female Sprague–Dawley rats remained sedentary or were exercise trained prior to saline or DOX exposure. Our findings demonstrate that DOX treatment elevated AST and AST/ALT in male rats, with no effects of exercise preconditioning to prevent these increases. We also showed increased plasma markers of renin–angiotensin–aldosterone system (RAAS) activation and urine markers of proteinuria and proximal tubule damage, with male rats revealing greater differences compared to females. Exercise preconditioning showed improved urine creatinine clearance and reduced cystatin c in males, while females had reduced plasma angiotensin II (AngII) levels. Our results demonstrate both tissue- and sex-specific responses related to the effects of exercise preconditioning and DOX treatment on markers of liver and kidney toxicity. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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Review

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22 pages, 1109 KiB

Open AccessReview

Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use

by Rolf Teschke and Gaby Danan

Int. J. Mol. Sci. 2023, 24(13), 10855; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310855 - 29 Jun 2023

Cited by 2 | Viewed by 1720

Abstract

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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19 pages, 743 KiB

Open AccessReview

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

by Rolf Teschke

Int. J. Mol. Sci. 2023, 24(7), 6663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076663 - 03 Apr 2023

Cited by 3 | Viewed by 1634

Abstract

Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention. Full article

(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)

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