Chemico-Biological Interactions最新文献

{"title":"Recent progress of proline endopeptidase ligands and their effects on protein-protein interactions","authors":"Kun-Jie Bian ,&nbsp;Xiaoze Bao ,&nbsp;Xiao-Dong Li ,&nbsp;Damien Bonne ,&nbsp;Li-Wei Zou","doi":"10.1016/j.cbi.2025.111557","DOIUrl":"10.1016/j.cbi.2025.111557","url":null,"abstract":"<div><div>Proline endopeptidase (PREP), as a serine protease, plays a crucial role in human physiology and pathology, and is intricately linked to the genesis and progression of a spectrum of illnesses. The fluorescent substrates currently used for PREP lack ideal specificity and are unable to specifically detect PREP activity under physiological conditions. This limitation, to some extent, hinders the in-depth investigation of its physiological and pathophysiological functions. Beyond its enzymatic capabilities, PREP's physiological functions extend to the modulation of protein-protein interactions (PPIs), a dimension whose significance is only beginning to be recognized, and investigations into how PREP inhibitors might influence these PPIs remain sparse. Therefore, based on the outline of the distribution and structural characteristics of PREP, this review systematically summarized the structure-activity relationship (SAR) of PREP ligands concerning their potency and specificity, the associated recognition mechanisms, as well as the regulatory impact of PREP ligands on PPIs. Finally, the obstacles and future prospects of PREP ligands were emphasized, in order to provide suggestions and help for the design and development of PREP specific substrates and inhibitors.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111557"},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, cytotoxicity, oxidative stress, anti-metastatic and anti-inflammatory effects of novel 2-methylene-1H-indene-1,3-dione tethered 2-(2-methoxyphenoxy)-N-arylacetamide: induction of apoptosis in HCT116 and HeLa cells","authors":"Nada S. Ibrahim ,&nbsp;Eman Hatem Shoukry ,&nbsp;Marwa Sharaky ,&nbsp;Hadeer M. Diab ,&nbsp;Ahmed H.M. Elwahy ,&nbsp;Ismail A. Abdelhamid","doi":"10.1016/j.cbi.2025.111549","DOIUrl":"10.1016/j.cbi.2025.111549","url":null,"abstract":"<div><div>Six novel chalcones were synthesized, and their structures were confirmed using various spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against nine cancer and two normal cell lines. Compound <strong>7a</strong> showed the highest impact against colorectal carcinoma (HCT116) and cervical cancer (HeLa) with IC₅₀ values of 4.6 ± 0.03 and 5.5 ± 0.1 μg/mL, respectively, compared to doxorubicin (4.8 ± 0.4 and 5.7 ± 0.4 μg/mL, respectively). ELISA assay revealed that the apoptotic proteins (P53, Bax, caspases-3, -8, and -9) and the oxidative marker (Malondialdehyde (MDA)) were significantly activated in <strong>7a</strong> treated HCT116 and HeLa cells. However, the anti-metastatic markers (Matrix metalloproteinase 2 (MMP2) and Matrix metalloproteinase-9 (MMP9)), anti-apoptotic Bcl2, antioxidant Glutathione (GSH), and anti-inflammatory (interleukin (IL)-6, and IL-1β) were inhibited in HCT116 and HeLa cells treated with <strong>7a</strong>. Flow-cytometric analysis of the cell cycle revealed that the percentage of cells in S and G2/M phases in <strong>7a</strong> treated HCT116 cells was increased. After 24 h of treatment, Hela-treated cells had a slightly higher proportion of G0/G1 cells. Comet assay demonstrated that compound <strong>7a</strong> caused DNA damage with a percentage of 26.22 ± 1.1 % in HCT116 compared to the untreated cells (6.18 ± 0.88 %). Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of −22.7 and −23.3 kcal/mol, respectively, which confirmed our ELISA results.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111549"},"PeriodicalIF":4.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TET2 promotes UVB-induced cell death by activating RIPK3-MLKL-necroptosis signaling","authors":"Daijing Long ,&nbsp;Yangfan Xu ,&nbsp;Xuemei Li,&nbsp;Yilan Zeng,&nbsp;Ziting Tang,&nbsp;Lulu Liu,&nbsp;Yuanhong Liu,&nbsp;Xiule Zong,&nbsp;Shengbo Yang,&nbsp;Dan Wang","doi":"10.1016/j.cbi.2025.111550","DOIUrl":"10.1016/j.cbi.2025.111550","url":null,"abstract":"<div><div>Ultraviolet B(UVB) radiation is a leading environmental factor that induces severe photodamage. However, its pathogenic mechanisms remain incompletely understood. Our previous research has found that Ten-eleven translocation 2 (TET2) is significantly upregulated in UVB-irradiated keratinocytes. Here, this study revealed that TET2 was upregulated in photodamaged skin, including specimens from actinic keratosis (AK) patients, UVB-exposed human skin sites, and a photodamaged mouse model. TET2 deficiency in keratinocytes mitigated UVB-induced cell death and photodamage, while TET2 overexpression exacerbated these effects. Furthermore, TET2 prompted keratinocyte death and photodamage mainly by activating the RIPK3-MLKL signaling pathway, with caspase-8 activation contributing secondarily. As for the mechanism, firstly, TET2 increases the expression of RIPK3 and MLKL by promoting their DNA demethylation, and secondly, TET2 directs the binding of PLK3 to RIPK3 and MLKL, thus enhancing the RIPK3-MLKL signaling pathway activation. This work showed that TET2 increases UVB-induced keratinocyte death and photodamage by activating the RIPK3-MLKL signaling pathway. TET2 appears to have a second function that orchestrates host responses to UVB exposure.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111550"},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of thiosemicarbazides and 1,2,4-triazoles derived from ibuprofen as potential MetAP (type II) inhibitors","authors":"Özgür Yılmaz ,&nbsp;Yağmur Biliz ,&nbsp;Sümeyra Ayan ,&nbsp;Özge Çevik ,&nbsp;Müfide Karahasanoğlu ,&nbsp;Reyhan Çotuker ,&nbsp;Naz Mina Mert Şahin ,&nbsp;Kübra Gökkaya ,&nbsp;Sevgi Gülyüz ,&nbsp;Kemal Yelekçi ,&nbsp;Ş. Güniz Küçükgüzel","doi":"10.1016/j.cbi.2025.111555","DOIUrl":"10.1016/j.cbi.2025.111555","url":null,"abstract":"<div><div>In the present study, a range of novel thiosemicarbazides <strong>4a-i</strong> and 1,2,4-triazoles <strong>5a-i</strong> derived from ibuprofen, were synthesized. Structural elucidation of these synthesized compounds was performed utilizing a variety of spectroscopic methods, including FTIR, ¹H NMR, ¹³C NMR and HR-MS. The synthesized compounds were tested for cytotoxicity in five different cancer cell lines (cervical cancer (HeLa), human breast cancer (MCF-7), human gastric adenocarcinoma (MKN-45), human metastatic prostate cancer (PC3) and human glioblastoma (U87)). The compounds were compared with healthy cells (NIH-3T3) and the most effective compounds were determined by means of the selectivity index. Thiosemicarbazides derived form ibuprofen <strong>4i</strong> and <strong>4d</strong> showed anticancer activity, while 1,2,4-triazoles derived form ibuprofen <strong>5b, 5c, 5d, 5e, 5h, 5g</strong> showed anticancer activity in HeLa, MCF-7, MKN-45, PC3 and U87 cells. To test the stability of the protein-drug complexes all 18 compounds <strong>4a-i</strong> and <strong>5a-i</strong> were docked into the active site of the MetAP2 enzyme In general, computational inhibition constants values were correlated with the experimental values. The dynamic behavior of MetAP2-inhibitor complexes was analyzed using all atoms Molecular Dynamic (MD) simulations for 200 ns duration. MD revealed that the drugs bind in the active center of MetAP2 with stable RMSD and RMSF. In conclusion, in-silico results and in-vitro studies suggests that thiosemicarbazides and 1,2,4-triazoles derived from ibuprofen may be novel anticancer drug candidates for treating cervical, breast, prostate, gastric and glioblastoma. Compounds provided induction of apoptotic proteins in the cell by inhibiting MetAP2 enzyme. Furthermore, the potential antioxidant activities of the compounds were evaluated using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay. Among the compounds tested, <strong>4a</strong>, <strong>4b</strong>, <strong>4e</strong>, <strong>4f</strong>, <strong>4h</strong>, and <strong>4i</strong> exhibited values closely resembling the DPPH activity of the standards.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111555"},"PeriodicalIF":4.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of acute organophosphate poisoning by using a cocaine hydrolase engineered from human butyrylcholinesterase","authors":"Johnathan E. LeSaint ,&nbsp;Shurong Hou ,&nbsp;Nellore Bhanu Chandar ,&nbsp;Annet Kyomuhangi ,&nbsp;Huimei Wei ,&nbsp;Fang Zheng ,&nbsp;Chang-Guo Zhan","doi":"10.1016/j.cbi.2025.111552","DOIUrl":"10.1016/j.cbi.2025.111552","url":null,"abstract":"<div><div>Organophosphate (OP) chemical warfare nerve agents and pesticides are potent, irreversible inhibitors of acetylcholinesterase (AChE), and paraoxon is often used as a surrogate compound in the studies of OP poisoning. For a truly effective treatment of OP poisoning, it is desirable that a protein-based OP bioscavenger can react with OP significantly faster than AChE reacting with OP to protect AChE from further inhibition reaction with OP. In the present study, our <em>in vitro</em> reactivity assays revealed that CocH3-Fc(M3), a potent cocaine hydrolase engineered from human butyrylcholinesterase (BChE), has a ∼20-fold improved bimolecular rate constant for the reaction with paraoxon compared to wild-type BChE. Due to the improved <em>in vitro</em> reactivity with paraoxon, CocH3-Fc(M3) at a modest dose of 25 mg/kg was able to effectively rescue all mice that had been injected with a lethal dose of 0.66 mg/kg paraoxon and accelerate the recovery of the mice from paraoxon-induced toxicity symptoms. All the <em>in silico</em>, <em>in vitro</em>, and <em>in vivo</em> data consistently suggest that CocH3-Fc(M3) can be used to effectively detoxify paraoxon.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111552"},"PeriodicalIF":4.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of paraoxonase activity and prooxidant-antioxidant balance in the brain tissue of rats following subacute administration of different K-oximes","authors":"Vesna Jaćević ,&nbsp;Jelica Grujić-Milanović ,&nbsp;Zoran Milovanović ,&nbsp;Sladjan Milanović ,&nbsp;Lana Nežić ,&nbsp;Ljiljana Amidžić ,&nbsp;Nataša Vojinović ,&nbsp;Bojan Marković ,&nbsp;Vladimir Dobričić ,&nbsp;Petar Milosavljević ,&nbsp;Eugenie Nepovimova ,&nbsp;Kamil Kuča","doi":"10.1016/j.cbi.2025.111539","DOIUrl":"10.1016/j.cbi.2025.111539","url":null,"abstract":"<div><div>This study aimed to determine the paraoxonase activity and prooxidant-antioxidant balance in the brain tissue of Wistar rats following subacute treatment with selected K-oximes. Each K-oxime was administered intramuscularly (0.1 LD₅₀/kg) twice per week for four weeks, and 7 days after the last treatment, the paraoxonase activity (PON1), the prooxidant-antioxidant balance (PAB), the levels of superoxide anion radical (O₂^•–), the concentration of nitrite (NO₂⁻) and the content of free protein thiol groups in the brain homogenates were evaluated. The PON1 and PAB activity were significantly reduced in almost all oxime-treated groups (<em>p</em> &lt; 0.01 and <em>p</em> &lt; 0.001, respectively). The concentrations of O₂^•– were significantly increased in the obidoxime-, K048-, K074- and K075-treated groups (<em>p</em> &lt; 0.001), while the levels of NO₂⁻ was significantly decreased in asoxime-, obidoxime-, K074 and K075-treated rats (<em>p</em> &lt; 0.01, <em>p</em> &lt; 0.001, respectively). The content of Thiol groups was significantly elevated in all oxime-treated groups (<em>p</em> &lt; 0.001). Continuing our previously published data, these results confirmed that applied K-oximes improved the oxidative status and further harmful systemic effects of rats after subacute administration.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111539"},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Four germline POLH variants, including two found in skin tumors, impair DNA polymerase η function and cellular tolerance to UV radiation and cisplatin","authors":"Jin-Kyung Hong ,&nbsp;Mina Yeom ,&nbsp;Hye-Yeon Hwang ,&nbsp;Eunji Mun ,&nbsp;Jae-Hyeon Woo ,&nbsp;Yeho Kim ,&nbsp;Joo-Ho Shin ,&nbsp;Yunjong Lee ,&nbsp;Daesik Kim ,&nbsp;F. Peter Guengerich ,&nbsp;Jeong-Yun Choi","doi":"10.1016/j.cbi.2025.111551","DOIUrl":"10.1016/j.cbi.2025.111551","url":null,"abstract":"<div><div>DNA polymerase (pol) η is vital for accurately replicating DNA opposite ultraviolet light (UV)-induced cyclobutane pyrimidine dimers and cisplatin-induced intrastrand purine crosslinks. While human <em>POLH</em> deficiency is linked to the disease xeroderma pigmentosum variant, the functional consequences of germline and somatic <em>POLH</em> variants remain largely unexplored. We characterized nine nonsynonymous <em>POLH</em> germline variants, five of which have also been found in various tumors. Enzyme activity was first assessed using recombinant pol η (residues 1–432) proteins. Variants F17S, C227Y, and R356X displayed substantially reduced or nearly abolished polymerase activity opposite <em>cis</em>-<em>syn</em> cyclobutane thymine dimer (CTD) compared to the wild-type. Cellular effects were then evaluated in <em>POLH</em>-deficient human embryonic kidney (HEK) 293 cells. Unlike cells transfected with wild-type <em>POLH</em>, cells transfected with F17S, R81C, C227Y, or R356X variants failed to rescue UV- and cisplatin-sensitivity. Interestingly, the R81C variant protein was undetectable in transfected cells. Further steady-state kinetic analysis revealed that the F17S, C227Y, and R356X variants had 3- to 5000-fold reductions in <em>k</em>_cat/<em>K</em>_m values for correct dATP insertion opposite CTD, while the R81C variant exhibited kinetics comparable to the wild-type enzyme. CRISPR/Cas9-mediated knock-in of the R81C variant in HEK 293T cells was associated with significantly impaired pol η protein expression and increased cisplatin sensitivity. Notably, R81C and R356X mutations have been reported in skin cancer samples. These findings suggest that R81C, F17S, C227Y, and R356X <em>POLH</em> variants−underexpressed or hypoactive−may be insufficient to protect cells from UV radiation and cisplatin, highlighting their potential implications for individual susceptibility to UV and cisplatin damage.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111551"},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States","authors":"Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology &Pharmacology andCurrent Opinion in Toxicology) ,&nbsp;Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions,Computational Toxicology, andJournal of Toxicology andRegulatory Policy) ,&nbsp;Sonja von Aulock PhD (Editor-in-Chief,ALTEX –Alternatives to Animal Experimentation) ,&nbsp;Anna Bal-Price PhD (Editor-in-Chief,Reproductive Toxicology) ,&nbsp;Michael D. Coleman PhD (Editor-in-Chief,Environmental Toxicology andPharmacology) ,&nbsp;Mark T.D. Cronin PhD (Editor-in-Chief,Computational Toxicology) ,&nbsp;Paul Jennings PhD (Editor-in-Chief,Toxicology in Vitro) ,&nbsp;Angela Mally PhD (Editor-in-Chief,Toxicology Letters) ,&nbsp;Mathieu Vinken PhD (Editor-in-Chief,Toxicology andNAM Journal) ,&nbsp;Matthew C. Wright PhD (Editor-in-Chief,Food andChemical Toxicology)","doi":"10.1016/j.cbi.2025.111547","DOIUrl":"10.1016/j.cbi.2025.111547","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111547"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FB1 causes barrier damage to vascular endothelial cells through ferroptosis by a PINK1/Parkin mediated mitophagy-dependent mechanism","authors":"Zhang Shuxia ,&nbsp;Zhang Ping ,&nbsp;Zheng Xiaoyan ,&nbsp;Mao Sichao ,&nbsp;Xu Xinyi ,&nbsp;Kevin Waldron ,&nbsp;Wang Chenfeng ,&nbsp;Sherin R. Rouby ,&nbsp;Ahmed H. Ghonaim ,&nbsp;Chen Xingxiang","doi":"10.1016/j.cbi.2025.111536","DOIUrl":"10.1016/j.cbi.2025.111536","url":null,"abstract":"<div><div>Fumonisin B1 (FB1) is an environmental mycotoxin produced mainly by fungi of the genus <em>Fusarium</em>. Exposure to FB1 can lead to pulmonary edema in pigs, likely caused by damage to vascular endothelial cells, but the mechanism of FB1-induced damage was unknown. Here, we found that FB1 damages vascular endothelial cells through ferroptosis, marked by iron-dependent membrane lipid peroxidation, and through mitophagy, a selective autophagy that targets mitochondria. FB1 exposure reduced barrier-related gene expression and increased pro-inflammatory factors. Ferroptosis was evidenced by elevated iron, ROS, lipid peroxidation, and ferroptotic markers (TFR, ACSL4), alongside decreased GSH, SLC7A11, and GPX-4 levels in vascular endothelial cells. Importantly, the ferroptosis inhibitor, Ferrostatin-1, reversed the vascular endothelial cells’ barrier damage, inflammation, and ferroptosis caused by FB1. FB1-induced mitophagy was demonstrated by detecting decreased mitochondrial membrane potential and increased levels of mitophagy-related proteins. Surprisingly, silencing PINK1 using siRNA not only diminished mitophagy, cellular damage, and inflammatory responses induced by FB1, but also mitigated FB1-induced ferroptosis. In conclusion, this study demonstrates that FB1 causes vascular endothelial cell damage by ferroptosis in a mitophagy-dependent manner. This study thus lays a mechanistic foundation for the study of FB1 causing pulmonary edema in pigs and for exploring options for therapeutic intervention in conditions caused by this mycotoxin, which causes substantial harm to both human and animal health.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111536"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADMET parameters of tacrine and its metabolites confirm unsuitability of Sus scrofa f. domestica model to study tacrine-associated hepatotoxicity","authors":"M. Novak ,&nbsp;J. Bureš ,&nbsp;V. Radochová ,&nbsp;J. Pejchal ,&nbsp;L. Prchal ,&nbsp;O. Soukup","doi":"10.1016/j.cbi.2025.111548","DOIUrl":"10.1016/j.cbi.2025.111548","url":null,"abstract":"<div><div>Tacrine, the first approved drug against Alzheimer's disease (AD), was withdrawn from clinical use due to serious adverse effects. The main concern was the human hepatotoxicity, stemming probably from the liver biotransformation and clinically manifested as hepatocellular necrosis, and lobular hepatitis. Concerning the biotransformation, 7-OH-tacrine metabolite is generally suspected of being a precursor of toxic quinone methide, which binds to intracellular –SH proteins and/or depletes intracellular glutathione, and by that probably causes the hepatotoxicity. However, to study these toxic effects, proper animal model is needed to monitor the interspecies differences of metabolism. To fully describe <em>in vivo</em> ADMET parameters of tacrine, five experimental pigs (<em>Sus scrofa f. domestica</em>), as the most physiologically human-like <em>in vivo</em> model showing similar tacrine biotransformation, were used. We studied tacrine and its metabolites ADMET characteristics after both acute i.g. single dose and chronic 42 days p.o daily dose administration of 200 mg of tacrine.</div><div>Tacrine and its two major metabolites show T_max in plasma of 360 min, so the absorption is much slower than in human (T_max = 120 min) and are primarily distributed to the gastro-intestinal tract and CNS. Furthermore, due to the lower activity of CYP1A2 in pigs, tacrine is biotransformed much less efficiently than in humans. This study showed that tacrine accumulates only in adipose tissue, and organ histology and plasma biochemistry assessment revealed no signs of hepatotoxicity even after chronic tacrine administration. Pigs are therefore an unsuitable human-like animal model for evaluating tacrine toxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111548"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}