Toxicological Research最新文献

{"title":"Protective effects of cardamom aqueous extract against tamoxifen-induced pancreatic injury in female rats.","authors":"Hala Attia, Afraa Alzoubi, Nour Al-Anazi, Aliah Alshanwani, Naglaa El-Orabi, Alaa Alanteet, Raeesa Mohamad, Rehab Ali","doi":"10.1007/s43188-023-00198-w","DOIUrl":"10.1007/s43188-023-00198-w","url":null,"abstract":"<p><p>Tamoxifen (TAM) is a commonly used drug for breast cancer treatment. Although effective, TAM has deleterious effects on many organs. The toxic effects of TAM on the pancreas and the underlying mechanisms however, have not fully investigated. In the present study, we investigated the effects of TAM on the pancreatic tissue in female rats. We also examined whether cardamom aqueous extract (CAE) protects against TAM-induced pancreatic injury. TAM-intoxicated rats were injected with 45 mg/kg of TAM for 10 days, whereas rats in the CAE-treated group were administered 10 mL/kg of CAE for 20 days, starting 10 days prior to TAM administration. Treatment with TAM resulted in severe degeneration of the pancreatic acini and marked increases in the serum levels of pancreatic lipase, α-amylase, glucose, fatty acids and triglycerides along with decreased insulin serum levels. TAM led to oxidative stress as evident from a significant increase in the pancreatic levels of lipid peroxides and nitric oxide along with the depletion of reduced glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, inflammation was indicated by a significant increase in tumor necrosis factor-α and interleukin-6 levels, enhanced expression of the macrophage recruitment marker; CD68 as well as up-regulated protein levels of toll-like receptor 4 and nuclear factor kappa B and increased p-p38/MAPK ratio; which are important signals in the production of inflammatory cytokines. TAM also markedly increased the pancreatic levels of caspase-3 and BAX reflecting its apoptotic effects. The CAE treatment ameliorated all the biochemical and histological changes induced by TAM. The present study revealed, for the first time, that TAM has toxic effects on the pancreatic tissue through oxidative stress, inflammation and apoptotic effects. The present study also provides evidence that CAE exerts cytoprotective effects against these deleterious effects induced by TAM in the pancreatic tissue.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00198-w.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"721-737"},"PeriodicalIF":1.6,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two weeks dose range-finding and four weeks repeated dose oral toxicity study of a novel reversible monoamine oxidase B inhibitor KDS2010 in cynomolgus monkeys.","authors":"Kyung-Tai Kim, Doo-Wan Cho, Jae-Woo Cho, Wan-Jung Im, Da-Hee Kim, Jong-Hyun Park, Ki Duk Park, Young-Su Yang, Su-Cheol Han","doi":"10.1007/s43188-023-00182-4","DOIUrl":"10.1007/s43188-023-00182-4","url":null,"abstract":"<p><p>A novel reversible monoamine oxidase B inhibitor, KDS2010, has been developed as a therapeutic candidate for neurodegenerative diseases. This study investigated its potential toxicity in non-human primates before human clinical trials. Daily KDS2010 doses (25, 50, or 100 mg/kg) were orally administered to cynomolgus monkeys (1 animal/sex/group, 4 males and 4 females) for 2 weeks to determine the dose range. One male was moribund, and one female was found dead in the 100 mg/kg/day group. One male was also found dead in the 50 mg/kg/day group. The death was considered an adverse effect in both sexes since distal tubules/collecting duct dilation and hypertrophy in the epithelium of the papillary duct were observed in their kidneys. Based on dose range finding results, KDS2010 (10, 20, or 40 mg/kg/day) was administered orally for 4 weeks, and animals were given 2 weeks for recovery. No significant changes were observed during daily clinical observations and macro-and microscopic examinations, including body weight, food consumption, hematology, clinical chemistry, and organ weight. And, the kidney was seen as the primary target organ of KDS2010 in the 2 weeks study, but no adverse effect was observed in the 4 weeks study. Therefore, 40 mg/kg/day is considered the no-observed-adverse-effect level in both sexes of cynomolgus monkeys.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00182-4.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"693-709"},"PeriodicalIF":1.6,"publicationDate":"2023-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41149261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative roles of sphingosine kinase in liver pathophysiology.","authors":"Kyu Min Kim, Eun Jin Shin, Ji Hye Yang, Sung Hwan Ki","doi":"10.1007/s43188-023-00193-1","DOIUrl":"10.1007/s43188-023-00193-1","url":null,"abstract":"<p><p>Bioactive sphingolipids and enzymes that metabolize sphingolipid-related substances have been considered as critical messengers in various signaling pathways. One such enzyme is the crucial lipid kinase, sphingosine kinase (SphK), which mediates the conversion of sphingosine to the potent signaling substance, sphingosine-1-phosphate. Several studies have demonstrated that SphK metabolism is strictly regulated to maintain the homeostatic balance of cells. Here, we summarize the role of SphK in the course of liver disease and illustrate its effects on both physiological and pathological conditions of the liver. SphK has been implicated in a variety of liver diseases, such as steatosis, liver fibrosis, hepatocellular carcinoma, and hepatic failure. This study may advance the understanding of the cellular and molecular foundations of liver disease and establish therapeutic approaches via SphK modulation.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"549-564"},"PeriodicalIF":1.6,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41149219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A regional approach for health risk assessment of toxicants in plastic food containers.","authors":"Lan Binh Thi Nguyen, Nguyen Thi Thanh Truc, Ngoc Tran Thi Nguyen, Dinh Khang Vu, Byeong-Kyu Lee","doi":"10.1007/s43188-023-00194-0","DOIUrl":"10.1007/s43188-023-00194-0","url":null,"abstract":"<p><p>Plastic food containers are being used popularly, generating a waste of about 115 million tons in Vietnam. Such waste is causing environmental and health issues. This study conducted a field survey with 250 local people and selected 59 samples out of 135 plastic food containers collected in Go Vap district, Vietnam. Collected plastic samples identified compositions were PET 13.6%, PP 28.8%, PS 16.9%, and 40.7% undefined plastics. Collected plastic samples were classified based on the plastic type using recycling code and quantitatively analyzed with X-ray fluorescence spectroscopy method to assess concentrations of Cd, Sb, Pb, Hg, Sn, Cr, Br, Cl, and S. Most of these collected plastic samples (91.5%) were found to contain 8/9 hazardous substances and most elements contained in these plastics were below their standard thresholds. These elements in plastic samples could be divided as the result into three hazard groups: (1) high hazard group (Sb, Cl, and S); (2) medium hazard group (Cr, Br and Hg); and (3) low hazard groups (Cd, Pb and Sn). Among substances in the high hazard group, element Sb was assessed for its migration because only Sb is regulated in Vietnam in QCVN 12-1: 2011/BYT. Substances of Cl, S, Cr, Br, and Hg (group 1, 2) do not have regulations related to the method of decontamination. Thus, additional health risks need to be assessed using the USEtox model. Finally, this study proposed a screening process to assess the risk of toxicity of elements contained in plastic food containers through ISO 31000:2018.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00194-0.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"681-692"},"PeriodicalIF":1.6,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma.","authors":"Thuy-Trang T Vo, Quangdon Tran, Youngeun Hong, Hyunji Lee, Hyeonjeong Cho, Minhee Kim, Sungjin Park, Chaeyeong Kim, Choinyam Bayarmunkh, Damdindorj Boldbaatar, So Hee Kwon, Jisoo Park, Seon-Hwan Kim, Jongsun Park","doi":"10.1007/s43188-023-00195-z","DOIUrl":"10.1007/s43188-023-00195-z","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00195-z.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"669-679"},"PeriodicalIF":1.6,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41115409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxygen consumption rate to evaluate mitochondrial dysfunction and toxicity in cardiomyocytes.","authors":"Dohee Ahn, Ryeo-Eun Go, Kyung-Chul Choi","doi":"10.1007/s43188-023-00183-3","DOIUrl":"10.1007/s43188-023-00183-3","url":null,"abstract":"<p><p>The increase in the types and complexity of diseases has led to significant advances in diagnostic techniques and the availability of effective therapies. Recent studies have focused on the role of mitochondrial dysfunction in the pathogenesis of cardiovascular diseases (CVDs). Mitochondria are important organelles in cells that generate energy. Besides the production of adenosine triphosphate (ATP), the energy currency of cells, mitochondria are also involved in thermogenesis, control of intracellular calcium ions (Ca²⁺), apoptosis, regulation of reactive oxygen species (ROS), and inflammation. Mitochondrial dysfunction has been implicated in several diseases including cancer, diabetes, some genetic diseases, and neurogenerative and metabolic diseases. Furthermore, the cardiomyocytes of the heart are rich in mitochondria due to the large energy requirement for optimal cardiac function. One of the main causes of cardiac tissue injuries is believed to be mitochondrial dysfunction, which occurs via complicated pathways which have not yet been completely elucidated. There are various types of mitochondrial dysfunction including mitochondrial morphological change, unbalanced levels of substances to maintain mitochondria, mitochondrial damage by drugs, and mitochondrial deletion and synthesis errors. Most of mitochondrial dysfunctions are linked with symptoms and diseases, thus we focus on parts of mitochondrial dysfunction about fission and fusion in cardiomyocytes, and ways to understand the mechanism of cardiomyocyte damage by detecting oxygen consumption levels in the mitochondria.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"333-339"},"PeriodicalIF":1.6,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9749086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute toxicity assessment of nine organic UV filters using a set of biotests.","authors":"Stec Marcin,&nbsp;Astel Aleksander","doi":"10.1007/s43188-023-00192-2","DOIUrl":"https://doi.org/10.1007/s43188-023-00192-2","url":null,"abstract":"<p><p>UV filters in environmental compartments are a source of concern related to their ecotoxicological effects. However, little is known about UV filters' toxicity, particularly those released into the environment as mixtures. Acute toxicity of nine organic UV filters benzophenone-1, benzophenone-2, benzophenone-3, 4-methoxy benzylidene camphor, octocrylene, ethylhexyl methoxycinnamate, 2-ethylhexyl salicylate, homosalate, and butyl methoxydibenzoylmethane was determined. UV filter solutions were tested as single, binary, and ternary mixtures of various compositions. Single solutions were tested using a set of bio tests, including tests on saline crustaceans (<i>Artemia franciscana</i>), freshwater crustaceans (<i>Daphnia magna</i>), marine bacteria (<i>Aliivibrio fischeri</i>), and freshwater plants (<i>Lemna minor</i>). The tests represent different stages of the trophic chain, and hence their overall results could be used to risk assessment concerning various water reservoirs. The toxicity of binary and ternary mixtures was analyzed using the standardized Microtox^® method. Generally, organic UV filters were classified as acutely toxic. Octocrylene was the most toxic for <i>Arthemia franciscana</i> (LC₅₀ = 0.55 mg L^-1) and <i>Daphnia magna</i> (EC₅₀ = 2.66-3.67 mg L^-1). The most toxic against freshwater plants were homosalate (IC₅₀ = 1.46 mg L^-1) and octocrylene (IC₅₀ = 1.95 mg L^-1). Ethylhexyl methoxycinnamate (EC₅₀ = 1.38-2.16 mg L^-1) was the most toxic for marine bacteria. The least toxic for crustaceans and plants were benzophenone-1 (EC₅₀ = 6.15-46.78 mg L^-1) and benzophenone-2 (EC₅₀ = 14.15-54.30 mg L^-1), while 4-methoxy benzylidene camphor was the least toxic for marine bacteria (EC₅₀ = 12.97-15.44 mg L^-1). Individual species differ in their sensitivity to the tested organic UV filters. An assessment of the toxicity of mixtures indicates high and acute toxicity to marine bacteria after exposition to a binary mixture of benzophenone-2 with octocrylene, 2-ethylhexyl salicylate, or homosalate. The toxicity of mixtures was lower than single solutions predicting antagonistic interaction between chemicals.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"649-667"},"PeriodicalIF":2.3,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41144236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atg5 knockout induces alternative autophagy via the downregulation of Akt expression.","authors":"Hye-Gyo Kim, Myeong-Han Ro, Michael Lee","doi":"10.1007/s43188-023-00191-3","DOIUrl":"10.1007/s43188-023-00191-3","url":null,"abstract":"<p><p>Autophagy play contradictory roles in cellular transformation. We previously found that the knockout (KO) of autophagy-related 5 (Atg5), which is essential for autophagy, leads to the malignant transformation of NIH 3T3 cells. In this study, we explored the mechanism by which autophagy contributes to this malignant transformation using two transformed cell lines, Atg5 KO and Ras-NIH 3T3. Monomeric red fluorescent protein-green fluorescent protein-light chain 3 reporter and Cyto-ID staining revealed that Ras-NIH 3T3 cells exhibited higher basal autophagy activity than NIH 3T3 cells. Additionally, transformed cells, regardless of their Atg5 KO status, were more sensitive to autophagy inhibitors (SBI-0206965, chloroquine, and obatoclax) than the untransformed NIH 3T3 cells, suggesting that the transformed cells are more autophagy-dependent than the normal cells. Loss of Atg5 improved the cell viability and mobility, especially in Ras-NIH 3T3 cells. Furthermore, we discovered that autophagy was alternatively induced in a Rab9-dependent manner in Ras-NIH 3T3 and NIH 3T3/Atg5 KO cells. In particular, Atg5 KO cells showed reduced mTOR-mediated phosphorylation of Akt (pAkt S473), indicating the mTOR-independent occurrence of alternative autophagy in Atg5 KO cells. Therefore, our study provides evidence that alternative autophagy may contribute to tumorigenesis in cells with an impaired Atg5-dependent autophagy pathway.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00191-3.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"637-647"},"PeriodicalIF":1.6,"publicationDate":"2023-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41150170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endotoxin of <i>Porphyromonas gingivalis</i> amplifies the inflammatory response in hyperglycemia-induced zebrafish through a mechanism involving chitinase-like protein YKL-40 analogs.","authors":"Gizem Gündüz, Merih Beler, İsmail Ünal, Derya Cansız, Ebru Emekli-Alturfan, Kemal Naci Kose","doi":"10.1007/s43188-023-00190-4","DOIUrl":"10.1007/s43188-023-00190-4","url":null,"abstract":"<p><p><i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>), a key pathogen in periodontal diseases, is also associated with hyperglycemia-associated systemic diseases, including diabetes mellitus (DM). Gingipains are the most important endotoxins of <i>P. gingivalis,</i> and in vivo studies using gingipains are scarce. Zebrafish (<i>Danio rerio</i>) is a vertebrate with high physiological and genetic homology with humans that has multiple co-orthologs for human genes, including inflammation-related proteins. The aim of our study was to determine the effects of gingipain in a hyperglycemia-induced zebrafish model by evaluating inflammation, oxidant-antioxidant status, and the cholinergic system. Adult zebrafish were grouped into the control group (C), hyperglycemia-induced group subjected to 15 days of overfeeding (OF), gingipain-injected group (GP), and gingipain-injected hyperglycemic group (OF + GP). At the end of 15 days, an oral glucose tolerance test (OGTT) was performed, and fasting blood glucose (FBG) levels were measured. Lipid peroxidation (LPO), nitric oxide (NO), glutathione (GSH), glutathione S-transferase, catalase, acetylcholinesterase (AChE), alkaline phosphatase (ALP), and sialic acid (SA) levels were determined spectrophotometrically in the hepatopancreas. The expression levels of <i>tnf-⍺, il-1β, ins, crp,</i> and the acute phase protein YKL-40 analogs <i>chia.5</i> and <i>chia.6</i> were evaluated by RT‒PCR. After two weeks of overfeeding, significantly increased weight gain, FBG, and OGTT confirmed that the zebrafish were hyperglycemic. Increased oxidative stress, inflammation, and AChE and ALP activities were observed in both the overfeeding and GP groups. Amplification of inflammation and oxidative stress was evident in the OF + GP group through increased expression of crp, <i>il-1β</i>, <i>chia.5,</i> and <i>chia.6</i> and increased LPO and NO levels. Our results support the role of gingipains in the increased inflammatory response in hyperglycemia-associated diseases.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"625-636"},"PeriodicalIF":1.6,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone-induced toxicities in rats: comparative study with other mitochondrial uncouplers (2,4-dinitrophenol, OPC-163493 and tolcapone).","authors":"Yuki Inoue, Yuko Wada, Makoto Sato, Seiji Sato, Takashi Okamoto, Naohide Kanemoto","doi":"10.1007/s43188-023-00189-x","DOIUrl":"10.1007/s43188-023-00189-x","url":null,"abstract":"<p><p>FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) is known to inhibit oxidative phosphorylation as a protonophore, dissipating the proton gradient across the inner mitochondrial membrane. To understand the toxicity of FCCP, 3-day, 2- and 4-week repeated oral dose studies were performed in male rats. In the 3-day and 2-week repeated dose toxicity studies, observations included salivation, increased body temperature, and dead and moribund animals. Increased liver weight was observed in conjunction with hydropic degeneration and centrilobular necrosis of hepatocytes. In addition, pathological changes were observed in the pancreas, testis, epididymal duct, stomach and parotid gland. Electron microscopic examination revealed mitochondrial pleomorphism in the hepatocytes. Swelling of mitochondria was observed in the alpha cells and beta cells of the pancreas. Dilatation of rough endoplasmic reticulum, Golgi bodies and loss of secretory granules were also noted in the beta cells of the pancreas. FCCP was also compared with three other mUncouplers (DNP, OPC-163493 and tolcapone) with regard to in vitro mitochondrial uncoupling (mUncoupling) activities. FCCP produced the peak ΔOCR (oxygen consumption rate) at the lowest concentration (0.4 μM), followed by OPC-163493, tolcapone, and DNP, based on peak values in ascending order of concentration (2.5, 10, and 50 μM, respectively). Considering the relationship between the mUncoupling activity and toxicity profile of the four mUncouplers, there is no parallel relationship between the in vitro mUncoupling activity and the degree of in vivo toxicity. These findings may contribute to the efficient development of new mitochondrial uncoupler candidates.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00189-x.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"611-623"},"PeriodicalIF":1.6,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41177114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}