The Journal of toxicological sciences最新文献_第4页

Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities. 甲硫威和威威在大鼠和人肝脏和血浆中的代谢及其对PXR、CAR和PPARα活性的影响。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.677

Chieri Fujino, Y. Tamura, Satoko Tange, H. Nakajima, S. Sanoh, Yoko Watanabe, Naoto Uramaru, Hiroyuki Kojima, K. Yoshinari, S. Ohta, S. Kitamura

{"title":"Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities.","authors":"Chieri Fujino, Y. Tamura, Satoko Tange, H. Nakajima, S. Sanoh, Yoko Watanabe, Naoto Uramaru, Hiroyuki Kojima, K. Yoshinari, S. Ohta, S. Kitamura","doi":"10.2131/jts.41.677","DOIUrl":"https://doi.org/10.2131/jts.41.677","url":null,"abstract":"The oxidative, reductive, and hydrolytic metabolism of methiocarb and the hydrolytic metabolism of carbaryl by liver microsomes and plasma of rats or humans were examined. The effects of the metabolism of methiocarb and carbaryl on their nuclear receptor activities were also examined. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide, and a novel metabolite, methiocarb sulfone were detected. Methiocarb sulfoxide was oxidized to the sulfone by liver microsomes and reduced back to methiocarb by liver cytosol. Thus, the interconversion between methiocarb and the sulfoxide was found to be a new metabolic pathway for methiocarb by liver microsomes. The product of methiocarb hydrolysis, which is methylthio-3,5-xylenol (MX), was also oxidized to sulfoxide form by rat liver microsomes. The oxidations were catalyzed by human flavin-containing monooxygenase isoform (FMO1). CYP2C19, which is a human cytochrome P450 (CYP) isoform, catalyzed the sulfoxidations of methiocarb and MX, while CYP1A2 also exhibited oxidase activity toward MX. Methiocarb and carbaryl were not enzymatically hydrolyzed by the liver microsomes, but they were mainly hydrolyzed by plasma and albumin to MX and 1-naphthol, respectively. Both methiocarb and carbaryl exhibited PXR and PPARα agonistic activities; however, methiocarb sulfoxide and sulfone showed markedly reduced activities. In fact, when methiocarb was incubated with liver microsomes, the receptor activities were decreased. In contrast, MX and 1-naphthol showed nuclear receptor activities equivalent to those of their parent carbamates. Thus, the hydrolysis of methiocarb and carbaryl and the oxidation of methiocarb markedly modified their nuclear receptor activities.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117185054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

Body surface area measurement in laboratory miniature pigs using a computed tomography scanner. 用计算机断层扫描仪测量实验室小型猪的体表面积。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.637

Tadashi Itoh, M. Kawabe, T. Nagase, K. Endo, M. Miyoshi, K. Miyahara

{"title":"Body surface area measurement in laboratory miniature pigs using a computed tomography scanner.","authors":"Tadashi Itoh, M. Kawabe, T. Nagase, K. Endo, M. Miyoshi, K. Miyahara","doi":"10.2131/jts.41.637","DOIUrl":"https://doi.org/10.2131/jts.41.637","url":null,"abstract":"The body surface area (BSA) of an organism is an important parameter for evaluating physiological functions. In drug development, normalization by BSA is an appropriate method for extrapolating doses between species. The BSA of animals has generally been estimated by multiplying a constant by the power of the body weight (BW). Recently, the use of miniature pigs in non-clinical studies for medical drugs or devices has gradually been increasing. However, verification of their BSA is not as yet sufficient. In this study, we measured the BSAs of 40 laboratory miniature pigs (11 males and 9 females of Göttingen minipig and 14 males and 6 females of Nippon Institute for Biological Science [NIBS] miniature pig) by analyzing computed tomography (CT) images, since measurements using a CT scanner were expected to more precisely determine BSA than classical measuring techniques. The measurement results showed the BSAs of the 20 Göttingen minipigs to range from 0.4358 to 0.8356 m(2) (the working BW range: 12.7-37.0 kg) and 20 NIBS miniature pigs to range from 0.2906 to 0.8675 m(2) (the working BW range: 7.9-41.5 kg). Since accuracy and reproducibility were confirmed by measuring the surface area of an acrylic cuboid, we concluded the measurement method employed in this study to be very reliable. We propose the following estimating formula for BSA of laboratory miniature pigs: 100 × BSA [m(2)] = 7.98 × BW [kg](2/3).","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114175986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Exposure time-dependent thermal effects of radiofrequency electromagnetic field exposure on the whole body of rats. 射频电磁场暴露对大鼠全身的时间依赖性热效应。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.655

Shin Ohtani, A. Ushiyama, M. Maeda, K. Hattori, N. Kunugita, Jianqing Wang, Kazuyuki Ishii

{"title":"Exposure time-dependent thermal effects of radiofrequency electromagnetic field exposure on the whole body of rats.","authors":"Shin Ohtani, A. Ushiyama, M. Maeda, K. Hattori, N. Kunugita, Jianqing Wang, Kazuyuki Ishii","doi":"10.2131/jts.41.655","DOIUrl":"https://doi.org/10.2131/jts.41.655","url":null,"abstract":"We investigated the thermal effects of radiofrequency electromagnetic fields (RF-EMFs) on the variation in core temperature and gene expression of some stress markers in rats. Sprague-Dawley rats were exposed to 2.14 GHz wideband code division multiple access (W-CDMA) RF signals at a whole-body averaged specific absorption rate (WBA-SAR) of 4 W/kg, which causes behavioral disruption in laboratory animals, and 0.4 W/kg, which is the limit for the occupational exposure set by the International Commission on Non-Ionizing Radiation Protection guideline. It is important to understand the possible in vivo effects derived from RF-EMF exposures at these intensities. Because of inadequate data on real-time core temperature analyses using free-moving animal and the association between stress and thermal effects of RF-EMF exposure, we analyzed the core body temperature under nonanesthetic condition during RF-EMF exposure. The results revealed that the core temperature increased by approximately 1.5°C compared with the baseline and reached a plateau till the end of RF-EMF exposure. Furthermore, we analyzed the gene expression of heat-shock proteins (Hsp) and heat-shock transcription factors (Hsf) family after RF-EMF exposure. At WBA-SAR of 4 W/kg, some Hsp and Hsf gene expression levels were significantly upregulated in the cerebral cortex and cerebellum following exposure for 6 hr/day but were not upregulated after exposure for 3 hr/day. On the other hand, there was no significant change in the core temperature and gene expression at WBA-SAR of 0.4 W/kg. Thus, 2.14-GHz RF-EMF exposure at WBA-SAR of 4 W/kg induced increases in the core temperature and upregulation of some stress markers, particularly in the cerebellum.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"41 5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130804653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Sodium para-aminosalicylate protected cultured basal ganglia astrocytes from manganese-induced DNA damages and alteration of amino acid neurotransmitter levels. 对氨基水杨酸钠可保护培养的基底神经节星形细胞免受锰诱导的DNA损伤和氨基酸神经递质水平的改变。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.573

Shao-jun Li, Yi-Ni Luo, Yong Li, Jingwen Chen, Yuhuan Mo, Zongxiang Yuan, Shi-yan Ou, Chao-yan Ou, Yue-Ming Jiang, Xiang-fa Deng

{"title":"Sodium para-aminosalicylate protected cultured basal ganglia astrocytes from manganese-induced DNA damages and alteration of amino acid neurotransmitter levels.","authors":"Shao-jun Li, Yi-Ni Luo, Yong Li, Jingwen Chen, Yuhuan Mo, Zongxiang Yuan, Shi-yan Ou, Chao-yan Ou, Yue-Ming Jiang, Xiang-fa Deng","doi":"10.2131/jts.41.573","DOIUrl":"https://doi.org/10.2131/jts.41.573","url":null,"abstract":"Sodium para-aminosalicylate (PAS-Na) was first applied successfully in clinical treatment of two manganism patients with good prognosis. However, the mechanism of how PAS-Na protects against Mn-induced neurotoxicity is still elusive. The current study was conducted to explore the effects of PAS-Na on Mn-induced basal ganglia astrocyte injury, and the involvement of amino acid neurotransmitter in vitro. Basal ganglia astrocytes were exposed to 500 μM manganese chloride (MnCl2) for 24 hr, following by 50, 150, or 450 μM PAS-Na treatment for another 24 hr. MnCl2 significantly decreased viability of astrocytes and induced DNA damages via increasing the percentage of tail DNA and Olive tail moment of DNA. Moreover, Mn interrupted amino acid neurotransmitters by decreasing Gln levels and increasing Glu, Gly levels. In contrast, PAS-Na treatment reversed the aforementioned Mn-induced toxic effects on basal ganglia astrocytes. Taken together, our results demonstrated that excessive Mn exposure may induce toxic effects on basal ganglia astrocytes, while PAS-Na could protect basal ganglia astrocytes from Mn-induced neurotoxicity.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129219199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences. 转录组分析表明，过氧化物酶体增殖体激活受体α (PPARα)活性的紫外线吸收剂2-(2'-羟基-3'，5'-二叔丁基苯基)苯并三唑可能是其毒性和性别差异的机制。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.693

M. Hirata‐Koizumi, Ryota Ise, Hirohito Kato, T. Matsuyama, T. Nishimaki‐Mogami, Mika Takahashi, A. Ono, M. Ema, A. Hirose

{"title":"Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences.","authors":"M. Hirata‐Koizumi, Ryota Ise, Hirohito Kato, T. Matsuyama, T. Nishimaki‐Mogami, Mika Takahashi, A. Ono, M. Ema, A. Hirose","doi":"10.2131/jts.41.693","DOIUrl":"https://doi.org/10.2131/jts.41.693","url":null,"abstract":"2-(2'-Hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-irradiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132607349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Effects of pentobarbital, isoflurane, or medetomidine-midazolam-butorphanol anesthesia on bronchoalveolar lavage fluid and blood chemistry in rats. 戊巴比妥、异氟醚或美托咪定-咪达唑仑-丁托啡诺麻醉对大鼠支气管肺泡灌洗液和血液化学的影响。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.595

Y. Tsubokura, Toshio Kobayashi, Y. Oshima, N. Hashizume, M. Nakai, Shozo Ajimi, N. Imatanaka

{"title":"Effects of pentobarbital, isoflurane, or medetomidine-midazolam-butorphanol anesthesia on bronchoalveolar lavage fluid and blood chemistry in rats.","authors":"Y. Tsubokura, Toshio Kobayashi, Y. Oshima, N. Hashizume, M. Nakai, Shozo Ajimi, N. Imatanaka","doi":"10.2131/jts.41.595","DOIUrl":"https://doi.org/10.2131/jts.41.595","url":null,"abstract":"Bronchoalveolar lavage fluid (BALF) is commonly examined for pulmonary toxicity in animal studies. Two common means of anesthesia before euthanasia and bronchoalveolar lavage in rats are intraperitoneal injection of pentobarbital and inhalation of isoflurane. Medetomidine-midazolam-butorphanol is an alternative anesthesia to pentobarbital for animal welfare; however, the effect of this combination on BALF and blood chemistry is unknown. Here, we compared the effects of anesthesia by intraperitoneal injection of pentobarbital or one of two combinations of medetomidine-midazolam-butorphanol (dose, 0.375-2.0-2.5 or 0.15-2.0-2.5 mg/kg) or by inhalation of isoflurane on BALF and blood chemistry in rats with or without pulmonary inflammation. In BALF, we determined total protein, albumin, lactate dehydrogenase, total cell count and neutrophil count. In serum, we conducted a general chemistry screen. After anesthesia with pentobarbital or isoflurane, there were no significant differences between any of the BALF or blood chemistry parameters with or without inflammation. After anesthesia with either of the combinations of medetomidine-midazolam-butorphanol, lactate dehydrogenase, total cell count, neutrophil count, and almost all of the blood chemistry parameters were comparable with those observed after pentobarbital or isoflurane; however, BALF albumin and serum glucose were significantly increased in rats without inflammation. After the combination of low-dose medetomidine in rats with inflammation, BALF parameters were comparable with those observed after pentobarbital or isoflurane. Our results show that, of the anesthetics examined, inhalation of isoflurane is the most appropriate means of anesthesia when examining BALF or serum for toxicity studies in rats.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131869972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

N-methyl pyrrolidone (NMP) ameliorates the hypoxia-reduced osteoblast differentiation via inhibiting the NF-κB signaling. n -甲基吡咯烷酮(NMP)通过抑制NF-κB信号通路改善缺氧诱导的成骨细胞分化。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.701

Qiang Li, Rui Liu, Jianmin Zhao, Quanli Lu

{"title":"N-methyl pyrrolidone (NMP) ameliorates the hypoxia-reduced osteoblast differentiation via inhibiting the NF-κB signaling.","authors":"Qiang Li, Rui Liu, Jianmin Zhao, Quanli Lu","doi":"10.2131/jts.41.701","DOIUrl":"https://doi.org/10.2131/jts.41.701","url":null,"abstract":"Ischemic-hypoxic condition for local osteoblasts and bone mesenchymal stem cells during bone fracture inhibits bone repairing. N-methyl pyrrolidone (NMP) has been approved as a safe and biologically inactive small chemical molecule, and might be useful for bone fracture repairing. In the present study, we investigated the effect of NMP on the hypoxia-reduced cellular viability and the expression of differentiation-associated markers, such as bone morphogenetic protein 2 (BMP-2), propeptide of type I procollagen I (PINP), alkaline phosphatase (ALP) or runt-related transcription factor 2 (Runx2) in the osteoblasts, and then we examined the molecular mechanism underlining such effect in the human osteoblastic hFOB 1.19 cells. Our results demonstrated that NMP significantly blocked the hypoxia-induced cell viability reduction and inhibited the hypoxia-caused expression downregulation of BMP-2, PINP, ALP and Runx2 in hFOB 1.19 cells. Then we confirmed the involvement of nuclear factor κB (NF-κB) pathway in the regulation by NMP on the hypoxia-mediated the reduction of osteoblast differentiation. The upregulated expression and transcriptional activity of NF-κB, while the downregulated inhibitory κB expression by the hypoxia treatment was reversed by the treatment with 10 mM NMP. In conclusion, our study found a protective role of NMP in osteoblast differentiation in response to hypoxia, and such protection was through inhibiting the NF-κB signaling. This suggests that NMP might be a protective agent in bone fracture repairing.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127444047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

The sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate induces ER stress in human astrocytoma cells. 沙林样有机磷制剂甲基膦酸异丙酯可诱导人星形细胞瘤细胞内质网应激。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.617

Yosuke Arima, H. Shiraishi, A. Saito, K. Yoshimoto, A. Namera, R. Makita, Kazuhiro Murata, K. Imaizumi, Masataka Nagao

{"title":"The sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate induces ER stress in human astrocytoma cells.","authors":"Yosuke Arima, H. Shiraishi, A. Saito, K. Yoshimoto, A. Namera, R. Makita, Kazuhiro Murata, K. Imaizumi, Masataka Nagao","doi":"10.2131/jts.41.617","DOIUrl":"https://doi.org/10.2131/jts.41.617","url":null,"abstract":"Organophosphorus (OP) compounds such as sarin are toxic agents that irreversibly inhibit the enzyme acetylcholinesterase. A recent study showed that OP compounds also have multiple toxicity mechanisms, and another suggested that endoplasmic reticulum (ER) dysfunction contributes to OP toxicity. However, the signaling pathway and mechanisms involved are poorly understood. We examined whether the sarin-like OP agent bis(isopropyl methyl)phosphonate (BIMP), which exhibits toxicity similar to that of sarin, induced ER stress in human astrocytoma CCF-STTG1 cells. Our results demonstrate that BIMP exposure reduced cell viability. Moreover, it induced changes in mitochondrial membrane potential and increased cleavage of caspase 3. Treatment with BIMP increased the mRNA levels of the ER stress marker genes binding immunoglobulin protein (BiP) and the transcription factor C/EBP homologous protein (CHOP). Furthermore, BIMP increased the protein expressions and phosphorylation of BiP, CHOP, and protein kinase RNA-like ER kinase and the phosphorylation of eukaryotic translation initiation factor 2. Compared to BIMP treatment alone, pretreatment with the CHOP siRNA, siCHOP, decreased BIMP-dependent CHOP expression and improved CCF-STTG1 cell viability. Our findings suggest that BIMP induced mitochondrial dysfunction and apoptotic cell death event mediated by ER stress in CCF-STTG1 cells and that treatment targeted at managing ER stress has the potential to attenuate the toxicity of OP nerve agents.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"88 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132886057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Usefulness of in vitro combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury. 线粒体功能障碍和细胞凋亡的体外联合检测在评估特异性药物诱导肝损伤潜在风险中的作用。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.605

Keisuke Goda, Tadakazu Takahashi, Akio Kobayashi, T. Shoda, H. Kuno, S. Sugai

{"title":"Usefulness of in vitro combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury.","authors":"Keisuke Goda, Tadakazu Takahashi, Akio Kobayashi, T. Shoda, H. Kuno, S. Sugai","doi":"10.2131/jts.41.605","DOIUrl":"https://doi.org/10.2131/jts.41.605","url":null,"abstract":"Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown. Recently, many in vitro assays which indicate a possibility of the prediction of the idiosyncratic DILI have been reported. Among these, some in vitro assays focus on the effects of compounds on mitochondrial function and the apoptotic effects of compounds on human hepatocytes. In this study, we measured oxygen consumption rate (OCR) and caspase-3/7 activity as an endpoint of mitochondrial dysfunction and apoptosis, respectively, with human hepatocytes after treatment with compounds causing idiosyncratic DILI (troglitazone, leflunomide, ranitidine and diclofenac). Troglitazone and leflunomide decreased the OCR but did not affect caspase-3/7 activity. Ranitidine increased caspase-3/7 activity but did not affect the OCR. Diclofenac decreased the OCR and increased caspase-3/7 activity. Acetaminophen and ethanol, which are also hepatotoxicants but do not induce idiosyncratic DILI, did not affect the OCR or caspase-3/7 activity. These results indicate that a combination assay of mitochondrial dysfunction and apoptosis is useful for the estimation of potential risk of compounds to induce idiosyncratic DILI.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115229388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Hydrogen sulfide donor NaHS induces death of alveolar epithelial L2 cells that is associated with cellular shrinkage, transgelin expression and myosin phosphorylation. 硫化氢供体NaHS诱导肺泡上皮L2细胞死亡，与细胞萎缩、transgelin表达和肌球蛋白磷酸化有关。

The Journal of toxicological sciences Pub Date : 2016-10-01 DOI: 10.2131/jts.41.645

Yusuke Fujii, T. Funakoshi, Kana Unuma, Kanako Noritake, T. Aki, Koichi Uemura

{"title":"Hydrogen sulfide donor NaHS induces death of alveolar epithelial L2 cells that is associated with cellular shrinkage, transgelin expression and myosin phosphorylation.","authors":"Yusuke Fujii, T. Funakoshi, Kana Unuma, Kanako Noritake, T. Aki, Koichi Uemura","doi":"10.2131/jts.41.645","DOIUrl":"https://doi.org/10.2131/jts.41.645","url":null,"abstract":"Hydrogen sulfide (H2S) is a highly toxic gaseous molecule that causes death to humans exposed to high concentrations. H2S is absorbed into the body through the alveolar epithelium and other tissues. The aim of this study is to evaluate the molecular mechanism underling acute lung injury caused by the inhalation of high concentrations of H2S. Rat lung epithelium-derived L2 cells were exposed to a H2S donor, NaHS, at concentrations of 2-4 mM for 1-6 hr. NaHS caused shrinkage and death of the cells without caspase activation. An actin-binding protein, transgelin, was identified as one of the NaHS-inducible proteins in the cells. NaHS increased myosin light chain (MLC) phosphorylation, indicating that actomyosin-mediated cellular contractility and/or motility could be increased after NaHS exposure. The administration of ML-7, a myosin light chain kinase (MLCK) inhibitor, accelerated cell death after NaHS exposure. Based on these data, we conclude that the increase in MLC phosphorylation in response to NaHS exposure is a cellular protective reaction against NaHS toxicity. Enhancements in smooth muscle cell properties such as transgelin expression and actomyosin-mediated contractility/motility might be involved in cell survival after NaHS exposure.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122398038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10