Journal of Toxicological Sciences最新文献_第3页

A preliminary evaluation of the applicability of the in vitro to in vivo extrapolation approach to quantitative risk assessment. 初步评价体外到体内外推法在定量风险评估中的适用性。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.7

Kikuo Yoshida, Takaaki Umano, Takashi Yamada, Mariko Matsumoto

{"title":"A preliminary evaluation of the applicability of the in vitro to in vivo extrapolation approach to quantitative risk assessment.","authors":"Kikuo Yoshida, Takaaki Umano, Takashi Yamada, Mariko Matsumoto","doi":"10.2131/jts.51.7","DOIUrl":"10.2131/jts.51.7","url":null,"abstract":"The applicability of the in vitro to in vivo extrapolation (IVIVE) approach for the quantitative risk assessment of chemicals was evaluated using the results of mouse uterotrophic bioassays conducted by the Japanese Ministry of Health, Labour and Welfare. Five chemicals were selected. In the uterotrophic bioassay, three chemicals exhibited positive estrogenic activity, whereas two exhibited negative activity. These chemicals were active in 16 in vitro assays that investigated the key events from estrogen receptor (ER) binding (initiating event) to ER-induced proliferation, enabling us to derive IVIVE conversion factors using a physiologically based kinetic model. The oral equivalent doses (OEDs) that were extrapolated from the activity concentrations at the half-maximal response (AC50) and the cutoff point (ACC) were compared with those of other key events to determine the critical key event that plays the most important role in the occurrence of uterotrophic responses. For the three chemicals that exhibited positive estrogenic activity, the OEDs from the in vitro AC50 values for the determined critical events were within a factor of 2 of the lowest observed effect levels in the uterotrophic bioassay. In addition, the OEDs from the ACC values for the critical key events of the two chemicals that exhibited negative activity were higher than the highest dose tested in the bioassay. Based on these findings, the IVIVE approach was largely valid. However, the critical key events that significantly affect in vivo responses need to be appropriately determined to apply the IVIVE approach for the quantitative risk assessment of chemicals.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"7-18"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917887","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

Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells. 甲基汞通过抑制C17.2小鼠神经干细胞GPX4蛋白水平诱导铁下垂。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.101

Naoya Yamashita, Haruka Nozuki, Tomoshi Yamashita, Kyotaro Tsubaki, Ryoko Fukushima, Ryota Yamagata, Gi-Wook Hwang

{"title":"Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells.","authors":"Naoya Yamashita, Haruka Nozuki, Tomoshi Yamashita, Kyotaro Tsubaki, Ryoko Fukushima, Ryota Yamagata, Gi-Wook Hwang","doi":"10.2131/jts.51.101","DOIUrl":"10.2131/jts.51.101","url":null,"abstract":"The causative agent of Minamata disease, which is characterized primarily by severe central nervous system dysfunction, is methylmercury; however, the mechanisms underlying methylmercury toxicity remain unclear. Ferroptosis is a type of programmed cell death that is mediated by iron-dependent lipid peroxidation and methylmercury has long been suggested to cause neuronal damage via lipid peroxidation, although the detailed mechanism of this action remains unknown. In this study we therefore investigated the involvement of ferroptosis in methylmercury-induced neuronal cell death using C17.2 mouse neural stem cells. First, we examined the effects of various ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, and deferoxamine) on methylmercury-induced cell death. All the inhibitors tested attenuated methylmercury-induced cell death. We then examined the levels of intracellular reactive oxygen species and lipid peroxides, and found that these levels were increased prior to methylmercury-induced cell death. We also examined the levels of a cystine transporter (xCT/SLC7A11) and glutathione peroxidase 4 (GPX4), major factors involved in the suppression of ferroptosis. We found that both mRNA and protein levels of xCT were increased prior to methylmercury-induced cell death, whereas GPX4 mRNA levels were largely unaffected by methylmercury and its protein levels were decreased. C17.2 cells overexpressing FLAG-GPX4 exhibited greater resistance to methylmercury than control cells. These results indicate that methylmercury induces ferroptosis in C17.2 cells by suppressing GPX4 protein levels.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"101-109"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100354","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

Virtual internal exposures of lansoprazole administered to cytochrome P450 2C19 poor metabolizers estimated by simplified physiologically based pharmacokinetic modeling. 通过简化生理药代动力学模型估计兰索拉唑给细胞色素P450 2C19代谢不良者的虚拟内暴露。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.349

Makiko Shimizu, Koichiro Adachi, Yukia Shimura, Katsuhiro Ohyama, Yoichi Tanaka, Yoshiro Saito, Hiroshi Yamazaki

{"title":"Virtual internal exposures of lansoprazole administered to cytochrome P450 2C19 poor metabolizers estimated by simplified physiologically based pharmacokinetic modeling.","authors":"Makiko Shimizu, Koichiro Adachi, Yukia Shimura, Katsuhiro Ohyama, Yoichi Tanaka, Yoshiro Saito, Hiroshi Yamazaki","doi":"10.2131/jts.51.349","DOIUrl":"10.2131/jts.51.349","url":null,"abstract":"Although the importance of polymorphic cytochrome P450 2C19 (CYP2C19) in the metabolism of proton pump inhibitors is well recognized, genotyping patients for CYP2C19 before prescribing proton pump inhibitors is not currently recommended in some Asian countries. Adverse events in patients prescribed 30-mg lansoprazole alone have been reported in the Japanese Adverse Drug Event Report database. This study aimed to evaluate virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers using a simplified physiologically based pharmacokinetic (PBPK) model. The input parameters for the simplified PBPK model were based on reported plasma concentrations for 30-mg lansoprazole. For poor metabolizers, the in vivo hepatic intrinsic clearance value was reduced from 13.4 L/hr to 3.4 L/hr. For comparison, a population-based (full) model was used based on the incorporated parameters for lansoprazole (latest Simcyp Simulator version 25). High virtual plasma and hepatic maximum concentrations and the areas under the concentration-time curves of lansoprazole in the poor metabolizers were generated by the simplified and full PBPK models. These results suggest that virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers can be evaluated using PBPK modeling systems. Despite the limited references to CYP2C19 polymorphisms in current Asian drug labeling, such in silico information could be informative.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 6","pages":"349-356"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138478","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

Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention. 甲基汞和镉通过NRF2抑制和汞滞留的协同毒性。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.315

Yasukazu Takanezawa, Narumi Suda, Nayu Orimo, Ryosuke Nakamura, Yuka Ohshiro, Shimpei Uraguchi, Masako Kiyono

{"title":"Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention.","authors":"Yasukazu Takanezawa, Narumi Suda, Nayu Orimo, Ryosuke Nakamura, Yuka Ohshiro, Shimpei Uraguchi, Masako Kiyono","doi":"10.2131/jts.51.315","DOIUrl":"10.2131/jts.51.315","url":null,"abstract":"Methylmercury (MeHg) is a potent environmental toxicant that frequently coexists with other heavy metals, raising concerns about combined toxic effects. Increasing evidence indicates that co-exposure to multiple metals can lead to synergistic or greater-than-additive effects; however, the molecular mechanisms underlying such interactions remain poorly understood. Among the tested metals, only co-exposure with Cd markedly enhanced MeHg cytotoxicity. Here, our objective was to evaluate the impact of MeHg co-exposure on cytotoxicity of various heavy metals in HeLa cells. We used cell viability assays, western blot analysis, and reverse-transcription-quantitative polymerase chain reactions to determine toxicity. Co-treatment with MeHg significantly reduced cell viability compared with that of Cd alone. Mechanistically, MeHg suppressed nuclear factor erythroid 2-related factor 2 (NRF2) expression more strongly at earlier time points than Cd alone, thereby impairing antioxidant and detoxification responses. This suppression was accompanied by increased intracellular mercury (Hg) retention, leading to enhanced cytotoxicity. Our results provide a mechanistic basis for metal-metal interactions and highlight the importance of considering co-exposure scenarios in environmental risk assessment.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 5","pages":"315-320"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839807","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

Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy. 内质网应激反应在顺铂诱导的肌萎缩发展中的潜在参与。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.123

Shinki Soga, Hayato Nanri, Hiroyasu Sakai, Ryunosuke Ichikawa, Yuya Chigusa, Yui Urase, Shiori Yonamine, Takayuki Ogiwara, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Kumiko Ogawa

{"title":"Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy.","authors":"Shinki Soga, Hayato Nanri, Hiroyasu Sakai, Ryunosuke Ichikawa, Yuya Chigusa, Yui Urase, Shiori Yonamine, Takayuki Ogiwara, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Kumiko Ogawa","doi":"10.2131/jts.51.123","DOIUrl":"10.2131/jts.51.123","url":null,"abstract":"Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents-cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide-on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"123-130"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100395","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

Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex. 犬肾上腺皮质类固醇生成中断引起的药物性空泡损伤恢复期的病理特征。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.57

Ryo Daniel Obara, Yuki Kato, Yoshiji Asaoka, Hiroyuki Oka, Yukie Murata, Takeshi Izawa, Mitsuru Kuwamura

{"title":"Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex.","authors":"Ryo Daniel Obara, Yuki Kato, Yoshiji Asaoka, Hiroyuki Oka, Yukie Murata, Takeshi Izawa, Mitsuru Kuwamura","doi":"10.2131/jts.51.57","DOIUrl":"10.2131/jts.51.57","url":null,"abstract":"Steroidogenesis disruption caused by compounds causes vacuolar lesions in the adrenal cortex. However, research on the reversibility of compound-induced adrenal lesions remains limited. In a 4-week oral repeated-dose toxicity study with a 4-week recovery period in dogs, administration of S-637880-a compound that off-target inhibits steroid hormone synthesis in vitro-resulted in diffuse microvesicular vacuolation, which was considered to reflect excess lipid accumulation in adrenocortical cells. After the 4-week recovery period, these diffuse vacuolar lesions developed into characteristic multifocal macrovesicular vacuolation in the adrenal cortex, making it difficult to evaluate lesion reversibility. Immunohistochemical evaluation suggested that the histopathological changes observed after the recovery period reflected slow degeneration of lipid-laden adrenocortical cells, culminating in cell death accompanied by macrophage activation and aggregation to process apoptotic or necrotic cells and the liberated lipids. These findings are considered to represent a transitional phase in the recovery process. The reversibility of S-637880-induced vacuolar lesions was confirmed in a subsequent 13-week oral repeated-dose toxicity study with a 13-week recovery period. This case study may be helpful in evaluating the reversibility of vacuolar lesions in the adrenal cortex during nonclinical safety assessments and in determining an appropriate recovery periods for assessing adrenal toxicity.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"57-73"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917899","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

False negatives in the modified ESR-based photosafety test (ESR-PT) caused by ultraviolet-C light. 改良esr光安全试验（ESR-PT）中紫外光引起的假阴性。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.1

Masumi Hinoshita, Yosuke Maeda, Akio Kawai, Masahiro Takeyoshi

{"title":"False negatives in the modified ESR-based photosafety test (ESR-PT) caused by ultraviolet-C light.","authors":"Masumi Hinoshita, Yosuke Maeda, Akio Kawai, Masahiro Takeyoshi","doi":"10.2131/jts.51.1","DOIUrl":"10.2131/jts.51.1","url":null,"abstract":"The modified electron spin resonance (ESR)-based photosafety test (ESR-PT) is a non-animal prediction test using ESR spectroscopy that is applicable to hydrophobic and colored chemicals and the results show high concordance with existing photosafety reference information. The modified ESR-PT is based on the detection of singlet oxygen and free radical photoproducts generated from chemicals in the presence of 4-hydroxy-2,2,6,6-tetramethyl-piperidine (4-hydroxy-TEMP). We obtained false-negative results caused by signal increment of the control solution, which is used as the denominator of the classifier in the modified ESR-PT, when we used a different type of lighting unit (type I) to the previously used type of lighting unit (type II). Spectral measurement of the irradiated light from the light sources revealed that the type I lighting unit emitted stronger UV-C light than the type II lighting unit. Consequently, as UV-C absorption of 4-hydroxy-TEMP (λmax<210 nm) was confirmed, we repeated the modified ESR-PT using a type I lighting unit equipped with a UV-C cut filter, which led to an apparent decrease of the signal increment in the control solution, and all the false-negative-judged chemicals correctly tested positive but a false positive result was also noted. Therefore, installation of a UV-C cut filter in the lighting unit in modified ESR-PT appears to be a reliable solution for avoiding UV-C light-mediated false-negative results. However, it may also be necessary to reconsider the classifier used in ESR-PT to avoid obtaining false-positive results when using a UV-C cut filter.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"1-6"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917926","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

Ordinal association between cytochrome P450 inhibition and hepatotoxicity severity in rats. 细胞色素P450抑制与大鼠肝毒性程度的有序关系。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.321

Nana Uchida, Minami Shibata, Akira Ooka, Ryota Shizu, Jun-Ichi Takeshita, Kouichi Yoshinari

{"title":"Ordinal association between cytochrome P450 inhibition and hepatotoxicity severity in rats.","authors":"Nana Uchida, Minami Shibata, Akira Ooka, Ryota Shizu, Jun-Ichi Takeshita, Kouichi Yoshinari","doi":"10.2131/jts.51.321","DOIUrl":"10.2131/jts.51.321","url":null,"abstract":"Cytochrome P450s (P450s) are essential for xenobiotic metabolism, and their inhibition is associated with chemical-induced liver toxicity. While qualitative associations between P450 inhibition and hepatotoxicity have been reported, the quantitative relationship between the degree of inhibition and the severity of hepatotoxicity remains unclear. In this study, we explored the quantitative association between P450 inhibition and hepatotoxicity using lowest observed effect levels (LOELs) from rat repeated-dose toxicity (RDT) studies on 326 chemicals. Inhibitory activities against seven rat P450 isoforms were compared between compounds positive and negative for six liver-related group endpoints (gEPs). The results revealed that inhibitory activity against CYP1A1, CYP2B1, CYP2C6, and CYP3A2 was significantly higher in compounds positive for hepatocellular hypertrophy or dyslipidemia than in negative compounds. Although regression analyses did not show clear linear relationships between P450 inhibition and LOELs, nonparametric trend tests revealed modest monotonic associations, with increased P450 inhibition corresponding to lower LOELs. To identify structural factors influencing inhibition among highly toxic compounds, we compared molecular descriptors between those exhibiting strong or weak P450 inhibition. Descriptors related to aqueous solubility, Verhaar baseline toxicity, and structural complexity were consistently higher in the weak-inhibition group across multiple P450-gEP combinations. These findings suggest that inhibition of CYP1A1, CYP2B1, CYP2C6, and CYP3A2 partly contributes to the severity of hepatocellular hypertrophy and dyslipidemia, whereas highly toxic compounds with low P450 inhibition may exert their toxicity through P450-independent mechanisms.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 5","pages":"321-330"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839834","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

Consideration of the applicability domain of an in silico physiologically based pharmacokinetic model for improving the predictivity of food-related compounds. 考虑一种基于计算机生理学的药代动力学模型的适用范围，以提高与食物有关的化合物的预测性。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.441

Takuya Kikuchi, Yuuki Takahashi, Ayako Yamada, Norie Arai, Maki Ishibashi, Daichi Fujita, Kazutoshi Saito

{"title":"Consideration of the applicability domain of an in silico physiologically based pharmacokinetic model for improving the predictivity of food-related compounds.","authors":"Takuya Kikuchi, Yuuki Takahashi, Ayako Yamada, Norie Arai, Maki Ishibashi, Daichi Fujita, Kazutoshi Saito","doi":"10.2131/jts.51.441","DOIUrl":"https://doi.org/10.2131/jts.51.441","url":null,"abstract":"The increasing demand for non-animal approaches in food safety assessment underscores the need for methods capable of predicting human internal exposure. We systematically evaluated the applicability of a physiologically based pharmacokinetic (PBPK) model-originally developed for pharmaceuticals and general chemicals, to predict physicochemical and pharmacokinetic parameters from chemical structure information and simulate human plasma profiles-to human internal exposure prediction. Food-related compounds were selected from published papers, and human single-dose pharmacokinetic studies were curated when all of the following criteria were met: 1) single administration in humans, 2) dose clearly specified as the target compound amount, 3) unchanged parent compound measured, 4) area under the curve (AUC) analyzed, and 5) no formulation/processing intended to control absorption. Using predicted parameters as PBPK inputs, peak plasma concentration (Cmax) and AUC were simulated and compared with observed values. In the absence of applicability restrictions, prediction ratios (predicted value/observed value) ranged from 0.00970 to 825 for Cmax and from 0.0000299 to 1628 for AUC; 20/36 Cmax and 19/40 AUC data points were within the three-fold error range (0.33-3). Restricting the applicability domain to compounds with predicted intestinal absorption/bioavailability > 0.5 and excluding a specific chemical-space region improved predictivity, with 11/12 (91.6%) Cmax and 9/12 (75.0%) AUC data points within the three-fold error range. Taken together, these results indicate that the in silico PBPK-based approach provides a practical and reasonably accurate estimate of human internal exposure for a subset of food-related compounds when an appropriate applicability domain is defined.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 8","pages":"441-448"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664151","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

Glyoxalase I inhibition by TLSC702 sensitizes glyoxalase I-dependent cancer cells to doxorubicin-induced cell death. TLSC702抑制乙醛化酶I使依赖乙醛化酶I的癌细胞对阿霉素诱导的细胞死亡敏感。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.565

Haruka Mori, Ryoko Takasawa

{"title":"Glyoxalase I inhibition by TLSC702 sensitizes glyoxalase I-dependent cancer cells to doxorubicin-induced cell death.","authors":"Haruka Mori, Ryoko Takasawa","doi":"10.2131/jts.51.565","DOIUrl":"https://doi.org/10.2131/jts.51.565","url":null,"abstract":"Glyoxalase I (GLO I) detoxifies the reactive glycolytic byproduct methylglyoxal (MG) and is frequently overexpressed in cancer cells. High GLO I expression is closely associated with resistance to anticancer drugs, including doxorubicin (DOX). However, the functional relationship between GLO I activity and DOX-induced cell death remains unclear. In this study, we investigated whether inhibition of GLO I enhances cellular sensitivity to DOX. Using non-small cell lung cancer cell lines with low (NCI-H460 cells) or high (NCI-H522 cells) GLO I expression, we found that NCI-H522 cells, which we previously reported to be highly sensitive to the GLO I inhibitor TLSC702 and to accumulate MG following GLO I inhibition, were more resistant to DOX than NCI-H460 cells. Cotreatment with exogenous MG significantly potentiated DOX-induced cytotoxicity through multiple cell death pathways, supporting a role for MG-related processes in modulating DOX responses. While simultaneous treatment with TLSC702 and DOX showed limited enhancement, pretreatment with TLSC702 followed by DOX markedly increased cell death in GLO I-high cells, suggesting that prior disruption of MG detoxification may sensitize cells to subsequent DOX exposure. This effect was accompanied by enhanced poly(ADP-ribose) polymerase (PARP) cleavage and was partially suppressed by caspase and autophagy inhibitors, indicating enhanced apoptosis with contributions from additional cell death pathways. Collectively, these results demonstrate that GLO I inhibition primes cancer cells for enhanced DOX-induced apoptosis, providing mechanistic insights into GLO I-associated chemoresistance.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 10","pages":"565-581"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111592","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