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Toxics
Special Issues
Drug Metabolism and Toxicological Mechanisms
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Drug Metabolism and Toxicological Mechanisms

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Drugs Toxicity".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 2551

Special Issue Editors

Prof. Dr. Qi Wang

E-Mail Website
Guest Editor
Department of Toxicology, Peking University, Beijing, China
Interests: cellular and computational toxicology
Dr. Youbo Zhang

E-Mail Website
Guest Editor
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Interests: natural products analysis; pharmacological research; nuclear receptor function; metabolic diseases
Special Issues, Collections and Topics in MDPI journals
Dr. An Zhu

E-Mail Website
Guest Editor
Research Centre of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
Interests: drug toxicology; computational toxicology; epitranscriptomics

Special Issue Information

Dear Colleagues,

Absorption, distribution, metabolism, and excretion (ADME) processes are of importance in understanding how the body disposes and responds to drugs. These processes play a pivotal role in assessing the efficacy and safety of drugs, while also enabling the prediction of potential adverse reactions or toxicities. A parent drug can undergo biotransformation by drug-metabolizing enzymes, leading to the formation of either toxic metabolites (metabolic activation) or non-toxic metabolites (detoxification). Thus, drug metabolism can be a key determinant of drug toxicity. Recently, new approach methodologies such as in silico methods, based on non-animal data, have been developed and applied in regulatory practices.

This Special Issue mainly focuses on drug metabolism and toxicological mechanisms. It extensively covers a range of topics, including drug metabolism, physiologically based pharmacokinetic (PBK) modeling, toxicokinetics–toxicodynamics (TK–TD), ADME characterization, the identification and toxicity of metabolites, high-throughput pharmacokinetics (HT-PK), organ-specific toxicity, and toxicological mechanisms.

Prof. Dr. Qi Wang
Dr. Youbo Zhang
Dr. An Zhu
Guest Editors

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. Toxics 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

  • drug metabolism
  • toxicity
  • mechanism
  • preclinical study
  • clinical trial

Published Papers (3 papers)

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Research

19 pages, 7555 KiB  
Article
Ribosomal Dysregulation in Metastatic Laryngeal Squamous Cell Carcinoma: Proteomic Insights and CX-5461’s Therapeutic Promise
by Miao Gao, Ting Liu, Kairui Hu, Songling Chen, Shixin Wang, Di Gan, Zhihan Li and Xiaohuang Lin
Toxics 2024, 12(5), 363; https://doi.org/10.3390/toxics12050363 - 13 May 2024
Viewed by 435
Abstract
One of the main barriers to the successful treatment of laryngeal squamous cell carcinoma (LSCC) is postoperative progression, primarily due to tumor cell metastasis. To systematically investigate the molecular characteristics and potential mechanisms underlying the metastasis in laryngeal cancer, we carried out a [...] Read more.
One of the main barriers to the successful treatment of laryngeal squamous cell carcinoma (LSCC) is postoperative progression, primarily due to tumor cell metastasis. To systematically investigate the molecular characteristics and potential mechanisms underlying the metastasis in laryngeal cancer, we carried out a TMT-based proteomic analysis of both cancerous and adjacent non-cancerous tissues from 10 LSCC patients with lymph node metastasis (LNM) and 10 without. A total of 5545 proteins were quantified across all samples. We identified 57 proteins that were downregulated in LSCC with LNM, which were enriched in cell adhesion pathways, and 69 upregulated proteins predominantly enriched in protein production pathways. Importantly, our data revealed a strong correlation between increased ribosomal activity and the presence of LNM, as 18 ribosomal subunit proteins were found to be upregulated, with RPS10 and RPL24 being the most significantly overexpressed. The potential of ribosomal proteins, including RPS10 and RPL24, as biomarkers for LSCC with LNM was confirmed in external validation samples (six with LNM and six without LNM) using Western blotting and immunohistochemistry. Furthermore, we have confirmed that the RNA polymerase I inhibitor CX-5461, which impedes ribosome biogenesis in LSCC, also decreases the expression of RPS10, RPL24, and RPS26. In vitro experiments have revealed that CX-5461 moderately reduces cell viability, while it significantly inhibits the invasion and migration of LSCC cells. It can enhance the expression of the epithelial marker CDH1 and suppress the expression of the mesenchymal markers CDH2, VIM, and FN at a dose that does not affect cell viability. Our study broadens the scope of the proteomic data on laryngeal cancer and suggests that ribosome targeting could be a supplementary therapeutic strategy for metastatic LSCC. Full article
(This article belongs to the Special Issue Drug Metabolism and Toxicological Mechanisms)
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25 pages, 8842 KiB  
Article
Integrating Epigenetics, Proteomics, and Metabolomics to Reveal the Involvement of Wnt/β-Catenin Signaling Pathway in Oridonin-Induced Reproductive Toxicity
by Qibin Wu, Xinyue Gao, Yifan Lin, Caijin Wu, Jian Zhang, Mengting Chen, Jiaxin Wen, Yajiao Wu, Kun Tian, Wenqiang Bao, Pengming Sun and An Zhu
Toxics 2024, 12(5), 339; https://doi.org/10.3390/toxics12050339 - 7 May 2024
Viewed by 513
Abstract
Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens, displaying anti-inflammatory, anti-tumor, and antibacterial effects. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis. Nevertheless, the clinical application of oridonin [...] Read more.
Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens, displaying anti-inflammatory, anti-tumor, and antibacterial effects. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis. Nevertheless, the clinical application of oridonin is significantly restricted due to its reproductive toxicity, with the exact mechanism remaining unclear. The aim of this study was to investigate the mechanism of oridonin-induced damage to HTR-8/SVneo cells. Through the integration of epigenetics, proteomics, and metabolomics methodologies, the mechanisms of oridonin-induced reproductive toxicity were discovered and confirmed through fluorescence imaging, RT-qPCR, and Western blotting. Experimental findings indicated that oridonin altered m6A levels, gene and protein expression levels, along with metabolite levels within the cells. Additionally, oridonin triggered oxidative stress and mitochondrial damage, leading to a notable decrease in WNT6, β-catenin, CLDN1, CCND1, and ZO-1 protein levels. This implied that the inhibition of the Wnt/β-catenin signaling pathway and disruption of tight junction might be attributed to the cytotoxicity induced by oridonin and mitochondrial dysfunction, ultimately resulting in damage to HTR-8/SVneo cells. Full article
(This article belongs to the Special Issue Drug Metabolism and Toxicological Mechanisms)
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17 pages, 7132 KiB  
Article
Biochemical Toxicological Study of Insulin Overdose in Rats: A Forensic Perspective
by Cunhao Bian, Xin He, Qi Wang, Zhe Zheng, Yongtai Zhang, Hongli Xiong, Yongguo Li, Mingzhu Zhao and Jianbo Li
Toxics 2024, 12(1), 17; https://doi.org/10.3390/toxics12010017 - 23 Dec 2023
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Abstract
Due to nonspecific pathological changes and the rapid degradation of insulin in postmortem blood samples, the identification of the cause of death during insulin overdose has always been a difficulty in forensic medicine. At present, there is a lack of studies on the [...] Read more.
Due to nonspecific pathological changes and the rapid degradation of insulin in postmortem blood samples, the identification of the cause of death during insulin overdose has always been a difficulty in forensic medicine. At present, there is a lack of studies on the toxicological changes and related mechanisms of an insulin overdose, and the specific molecular markers of insulin overdose are still unclear. In this study, an animal model of insulin overdose was established, and 24 SD rats were randomly divided into a control group, insulin overdose group, and a recovery group (n = 8). We detected the biochemical changes and analyzed the toxicological mechanism of an insulin overdose. The results showed that after insulin overdose, the rats developed irregular convulsions, Eclampsia, Opisthotonos, and other symptoms. The levels of glucose, glycogen, and C-peptide in the body decreased significantly, while the levels of lactate, insulin, and glucagon increased significantly. The decrease in plasma K+ was accompanied by the increase in skeletal muscle K+. The PI3K-AKT signaling pathway was significantly activated in skeletal muscle, and the translocation of GLUT4/Na+-K+-ATPase to sarcolemma was significantly increased. Rare glycogenic hepatopathy occurred in the recovery group after insulin overdose. Our study showed that insulin overdose also plays a role in skeletal muscle cells, mainly through the PI3K-Akt signaling pathway. Therefore, the detection of signaling pathway proteins of the skeletal muscle cell membrane GLUT4 and Na+-K+-ATPase has a certain auxiliary diagnostic value for forensic insulin overdose identification. Glycogen detection in the liver and skeletal muscle is important for the diagnosis of insulin overdose, but it still needs to be differentiated from other causes of death. Skeletal muscle has great potential for insulin detection, and the ratio of insulin to the C-peptide (I:C) can determine whether an exogenous insulin overdose is present. Full article
(This article belongs to the Special Issue Drug Metabolism and Toxicological Mechanisms)
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