Journal of Toxicological Sciences最新文献_第6页

Identification of post-mortem product of zolpidem degradation by hemoglobin via the Fenton reaction. 通过芬顿反应鉴定血红蛋白降解唑吡坦的尸检产物。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.261

Yoshikazu Yamagishi, Sayaka Nagasawa, Hirotaro Iwase, Yasumitsu Ogra

{"title":"Identification of post-mortem product of zolpidem degradation by hemoglobin via the Fenton reaction.","authors":"Yoshikazu Yamagishi, Sayaka Nagasawa, Hirotaro Iwase, Yasumitsu Ogra","doi":"10.2131/jts.49.261","DOIUrl":"10.2131/jts.49.261","url":null,"abstract":"Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In forensic toxicology, the precise determination of zolpidem concentration in blood is a must to provide concrete evidence of death by zolpidem poisoning. However, the concentrations of zolpidem in blood at autopsy often differ from those at the estimated time of death. In the present study, we found that zolpidem was degraded by hemoglobin (Hb) via the Fenton reaction at various temperatures. The mechanism underlying zolpidem degradation involved the oxidation of its linker moiety. The MS and MS/MS spectra obtained by liquid chromatography quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) showed the formation of 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide (2-OH ZOL) in Hb/H2O2 solution incubated with zolpidem and in the blood of several individuals who died from ingestion of zolpidem. These results suggest that 2-OH ZOL is the post-mortem product of zolpidem degradation by Hb via the Fenton reaction.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 6","pages":"261-268"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Validation of a new protocol for a zebrafish MEFL (malformation or embryo-fetal lethality) test method that conforms to the ICH S5 (R3) guideline. 验证符合 ICH S5 (R3) 指南的斑马鱼畸形或胚胎-胎儿致死率（MEFL）检测方法新方案。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.337

Kanako Mori, Yoshinobu Aoki, Fumito Mikashima, Kazushige Maki, Toshio Tanaka, Mai Hayashi, Wataru Sugimoto, Mizuho Ono, Saaya Umekita, Tatsuhiro Niino, Michio Fujiwara, Tomonori Ebata, Hiromi Hirata, Hajime Kojima

{"title":"Validation of a new protocol for a zebrafish MEFL (malformation or embryo-fetal lethality) test method that conforms to the ICH S5 (R3) guideline.","authors":"Kanako Mori, Yoshinobu Aoki, Fumito Mikashima, Kazushige Maki, Toshio Tanaka, Mai Hayashi, Wataru Sugimoto, Mizuho Ono, Saaya Umekita, Tatsuhiro Niino, Michio Fujiwara, Tomonori Ebata, Hiromi Hirata, Hajime Kojima","doi":"10.2131/jts.49.337","DOIUrl":"https://doi.org/10.2131/jts.49.337","url":null,"abstract":"Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 8","pages":"337-348"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Resin monomers induce apoptosis of the pulp-dentin complex through the mitochondrial pathway. 树脂单体通过线粒体途径诱导牙本质复合物的凋亡。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.531

Siqi Xu, Lijuan Chen, Xi Lin, Xiaoxia Yang, Lidan He, Siqi Yan, Song Luo, Xinyi Chen, Guoying Que

{"title":"Resin monomers induce apoptosis of the pulp-dentin complex through the mitochondrial pathway.","authors":"Siqi Xu, Lijuan Chen, Xi Lin, Xiaoxia Yang, Lidan He, Siqi Yan, Song Luo, Xinyi Chen, Guoying Que","doi":"10.2131/jts.49.531","DOIUrl":"https://doi.org/10.2131/jts.49.531","url":null,"abstract":"Numerous studies have confirmed that the apoptosis induced by the methacrylate resin monomers triethyleneglycol-dimethacrylate (TEGDMA), 2-hydroxy ethyl methacrylate (HEMA), etc., in pulp cells and odontoblast-like cells is caused mainly by oxidative stress (OS). Reactive oxygen species (ROS), recognized as the most important risk factor for apoptosis in cells of the pulp-dentin complex, are produced mainly via the mitochondrial respiratory chain. When the free resin monomers in the oral cavity and pulp reach a toxic level, the monomers induce oxidative DNA damage, activate ATM-p53 in the nucleus, and mediate the intrinsic apoptotic pathway in the presence of Bcl-2 family proteins. A vicious cycle is established between OS cellular responses and abnormalities in mitochondrial dynamics that accelerate apoptosis. Despite numerous products generated via iteration, complete polymerization of resin monomers is not currently possible. The cytotoxicity of free monomers may lead to adverse reactions, such as pulp sensitivity. This review is based on the most important papers describing the roles of resin monomers in mediating apoptosis in the pulp-dentin complex and provides an overview of the precise mechanisms related to mitochondrion-mediated cytotoxicity, suggesting ways to reduce or eliminate their cytotoxicity in the future through advancements in material technology.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 12","pages":"531-541"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nafamostat mesylate sensitizes ovarian cancer cells to carboplatin by promoting the ZNF24-mediated inhibition of WNT2B. 甲磺酸萘莫司他通过促进 ZNF24 介导的 WNT2B 抑制作用，使卵巢癌细胞对卡铂敏感。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.467

Jiehuan Xu, Jianlin Chen, Dao Wang, Yaojun Li, Ping Lian, Xiaozhu Wu, Rong Yan

{"title":"Nafamostat mesylate sensitizes ovarian cancer cells to carboplatin by promoting the ZNF24-mediated inhibition of WNT2B.","authors":"Jiehuan Xu, Jianlin Chen, Dao Wang, Yaojun Li, Ping Lian, Xiaozhu Wu, Rong Yan","doi":"10.2131/jts.49.467","DOIUrl":"https://doi.org/10.2131/jts.49.467","url":null,"abstract":"Resistance to chemotherapeutic medicines complicates and eventually kills people with ovarian cancer. Nafamostat mesylate (NM) has been used as an adjuvant therapy to enhance chemotherapy sensitivity in several cancers. This study aimed to evaluate the effect of NM on ovarian cancer cells susceptible to carboplatin (CBP) and to determine the underlying mechanism involved. Herein, qRT-PCR, western blot, and IHC were used to analyze mRNA and protein expression. Cell viability and proliferation were measured using the MTT and colony formation assays. Cell migration and invasion were examined using the Transwell assay. Flow cytometry was employed to detect cell apoptosis. The interaction between zinc finger protein 24 (ZNF24) and wingless-type MMTV integration site family member 2b (WNT2B) was validated via the dual-luciferase reporter and Chromatin immunoprecipitation assays. A xenograft nude mouse model was used to assess the effect of NM on CBP sensitivity in vivo. Our results showed that NM intervention inhibited the viability, proliferation, migration, and invasion and facilitated the apoptosis of CBP-resistant ovarian cancer cells. Furthermore, NM sensitized ovarian cancer cells to CBP by upregulating ZNF24. ZNF24 inactivated Wnt/β-catenin signaling by inhibiting the transcription of WNT2B. Additionally, NM enhanced the inhibitory effect of CBP on tumor growth in vivo. Taken together, NM enhanced the CBP sensitivity of ovarian cancer cells by promoting the ZNF24-mediated inactivation of the WNT2B/Wnt/β-catenin axis. These findings suggest a viable treatment approach for improving CBP resistance in ovarian cancer.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 11","pages":"467-479"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration. 单剂量氯虫苯甲酰胺会在成年期诱发不同性别的行为变化，具体取决于给药的发育阶段。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.301

Kenshi Kaku, Takahiro Sasaki, Kenshiro Hara, Kentaro Tanemura

{"title":"A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration.","authors":"Kenshi Kaku, Takahiro Sasaki, Kenshiro Hara, Kentaro Tanemura","doi":"10.2131/jts.49.301","DOIUrl":"https://doi.org/10.2131/jts.49.301","url":null,"abstract":"Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stages, studies that comprehensively evaluate both males and females are limited. Therefore, in this study we utilized murine models to compare the sex-specific differences in behavioral effects following CLO exposure at different developmental stages. We orally administered CLO to male and female mice as a single high-dose solution (80 mg/kg) during the postnatal period (2-week-old), adolescence (6-week-old), or maturity (10-week-old), and subsequently evaluated higher brain function. The behavioral battery test consisted of open field, light/dark transition, and contextual/cued fear conditioning tests conducted at three and seven months of age. After the behavioral test, the brains were dissected and prepared for immunohistochemical staining. We observed behavioral abnormalities in anxiety, spatial memory, and cued memory only in female mice. Moreover, the immunohistochemical analysis showed a reduction in astrocytes within the hippocampus of female mice with behavioral abnormalities. The behavioral abnormalities observed in female CLO-treated mice were consistent with the typical behavioral abnormalities associated with hippocampal astrocyte dysfunction. It is therefore possible that the CLO-induced behavioral abnormalities are at least in part related to a reduction in astrocyte numbers. The results of this study highlight the differences in behavioral effects following CLO exposure between sexes and developmental stages.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 7","pages":"301-311"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of food restriction on toxicological parameters in juvenile rats. 食物限制对幼鼠毒理学参数的影响

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.321

Yuko Izumi, Tomoya Sano, Yusuke Sudo, Kiyoshi Matsumoto

{"title":"Effects of food restriction on toxicological parameters in juvenile rats.","authors":"Yuko Izumi, Tomoya Sano, Yusuke Sudo, Kiyoshi Matsumoto","doi":"10.2131/jts.49.321","DOIUrl":"https://doi.org/10.2131/jts.49.321","url":null,"abstract":"To examine the effects of decreased food consumption on toxicological parameters in juvenile rats, rats on postnatal day 21 were fed 40%, 50% (only four weeks), and 60% less food, compared to that of controls for four or eight weeks, and clinical observations, measurement of body and organ weights, morphological differentiation analysis, clinical pathology, and macroscopic and microscopic examinations were conducted. The body weight decreased depending on the degree of food restriction (FR). Cleavage of the balano-preputial skinfold was delayed, and cell debris in the epididymal lumen was noted as a related finding after four-week FR. Vaginal opening was also delayed, and some histopathological findings, such as absence of corpus luteum in the ovary, mucinous degeneration in the vagina, and immature uterus, were noted after eight-week FR. Erythrocyte count increased after four-week FR, but slightly decreased in males only after eight-week FR, and decreased leukocyte and/or reticulocyte counts, accompanied by related histopathological findings were noted after four- and eight-week FR. In blood chemistry, the levels of total protein including globulin, glucose, triglyceride, and calcium decreased, and sodium and chloride increased after four- and eight-week FR. Increases in activities of aspartate transaminase and lactate dehydrogenase and total bilirubin levels were noted after four-week FR, which were attenuated after eight-week FR. The effects of FR seemed to be more remarkable after four weeks. In drug safety evaluation, findings caused by malnutrition should be considered in juvenile toxicity studies when decreased food consumption is observed.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 7","pages":"321-335"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxycodone alleviates LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis. 羟考酮通过调节 CREB/miR-181c/PDCD4 轴减轻 LPS 诱导的神经炎症。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.435

QingYun Tan, Kai Zhang, QingDong Wang, Rongjia Zang

{"title":"Oxycodone alleviates LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis.","authors":"QingYun Tan, Kai Zhang, QingDong Wang, Rongjia Zang","doi":"10.2131/jts.49.435","DOIUrl":"10.2131/jts.49.435","url":null,"abstract":"Background: Neuroinflammation plays a critical role in various neurological disorders. Oxycodone has anti-inflammatory properties. The purpose of this work was to look into the effect of oxycodone in controlling lipopolysaccharide (LPS)-induced neuroinflammation in microglia.Methods: LPS-induced HMC3 cells were subjected to oxycodone (2.5, 5, 10 and 20 μg/mL). The mRNA and protein expressions were examined by qRT-PCR and western blotting. TNF-α, IL-1β, IL-6, and IL-8 levels were assessed by ELISA. MTT assay was adopted to measure cell viability. The interactions between CREB, miR-181c and PDCD4 were analyzed by dual-luciferase reporter assay, ChIP and/or RIP assays.Results: Oxycodone treatment alleviated LPS-induced inflammation in HMC3 cells and increased p-CREB level, but reduced PDCD4 and iNOS levels in LPS-treated cells. Mechanistically, oxycodone mitigated LPS-induced neuroinflammation by upregulating miR-181c. In addition, CREB promoted miR-181c expression by directly binding to the MIR181C promoter, and miR-181c inhibited PDCD4 expression by directly binding to PDCD4 3'UTR. As expected, oxycodone alleviated LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis.Conclusion: Oxycodone attenuated LPS-induced neuroinflammation in microglia by regulating the CREB/miR-181c/PDCD4 axis. These findings proved that oxycodone is a potential drug for treating neuroinflammation and elucidate the mechanisms involved.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 10","pages":"435-446"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975. 新型强效转录增强关联域（TEAD）抑制剂 K-975 对大鼠肾脏的可逆和可监测毒性。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.175

Hironori Otsuki, Takeshi Uemori, Yohei Inai, Yui Suzuki, Tetsuro Araki, Ken-Ichiro Nan-Ya, Kouichi Yoshinari

{"title":"Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975.","authors":"Hironori Otsuki, Takeshi Uemori, Yohei Inai, Yui Suzuki, Tetsuro Araki, Ken-Ichiro Nan-Ya, Kouichi Yoshinari","doi":"10.2131/jts.49.175","DOIUrl":"10.2131/jts.49.175","url":null,"abstract":"The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 4","pages":"175-191"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated in silico as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances. 利用反相液相色谱法中的保留时间估算出的辛醇/水分配系数，并将其作为一般化学物质药代动力学参数估计的决定因素之一进行硅计算。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.127

Koichiro Adachi, Makiko Shimizu, Fumiaki Shono, Kimito Funatsu, Hiroshi Yamazaki

{"title":"Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated in silico as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances.","authors":"Koichiro Adachi, Makiko Shimizu, Fumiaki Shono, Kimito Funatsu, Hiroshi Yamazaki","doi":"10.2131/jts.49.127","DOIUrl":"10.2131/jts.49.127","url":null,"abstract":"The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance's in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 4","pages":"127-137"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bridging toxicological properties of environmental chemicals between animals and humans using healthy organoid systems. 利用健康的类器官系统，在动物和人类之间架起环境化学物质毒理学特性的桥梁。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.425

Toshio Imai, Rikako Ishigamori, Mie Naruse, Masako Ochiai, Yoshiaki Maru, Yoshitaka Hippo, Yukari Totsuka

{"title":"Bridging toxicological properties of environmental chemicals between animals and humans using healthy organoid systems.","authors":"Toshio Imai, Rikako Ishigamori, Mie Naruse, Masako Ochiai, Yoshiaki Maru, Yoshitaka Hippo, Yukari Totsuka","doi":"10.2131/jts.49.425","DOIUrl":"https://doi.org/10.2131/jts.49.425","url":null,"abstract":"The application of organoids derived from animal tissues and human-induced pluripotent stem cells to safety assessments of environmental chemicals has been introduced over the last decade. One of the objectives of this approach is to develop an alternative method for animal toxicological studies, while another is to focus on the local reactions of chemicals in each organ/tissue. One of the most important goals is bridging the toxicological properties of chemicals between animals and humans, which may be compared on a level playing field using healthy organoids derived from both animals and humans in vitro, excluding species difference in the absorption, distribution, metabolism, and excretion properties of chemicals in vivo. An overview of the application of organoid systems to safety assessments of environmental chemicals, including general toxicology, developmental toxicology, carcinogenicity, and mutagenicity, was provided herein, and bridging strategies using both animal and human organoids are proposed as a future perspective.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 10","pages":"425-434"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0