著者

Yoshitaka Hirasawa Atsushi Fujiwara Kazuya Tabata Kenji Yoshida Tsutomu Negama Takayuki Anzai Shin-ichi Sato

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.7, no.2, pp.105-114, 2020 (Released:2020-03-27)

参考文献数

33

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The purpose of this study was to profile cytokine storms (cytokine release syndrome) in the LPS-induced disseminated intravascular coagulation (DIC)-cynomolgus monkey model by measuring changes in 22 cytokines using Luminex. In this study, increases were noted in 20 cytokines, excluding IL-4 and IL-17A. Specifically, IL-6, IL-8, G-CSF and TNF-α, pro-inflammatory cytokines, and IL-10, an anti-inflammatory cytokine, as well as MCP-1, markedly increased by 10,000 pg/mL or more. In addition to the marked increases in the pro-inflammatory cytokines IL-6 and G-CSF, the concentrations of IL-5, IL-18, IFN-γ, VEGF and IL-15 increased continuously. Also, in addition to the marked increases in the pro-inflammatory cytokine IL-8 as well as in MCP-1, the concentrations of IL-1ra, IL-2, IL-1β, IL-12/23 (p40), GM-CSF and TGF-α gradually decreased after initially increasing. On the other hand, in addition to the marked increases in the pro-inflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10, MIP-1β and MIP-1α transiently increased and then rapidly disappeared from serum. IL-13 increased at 6 hr after administration only. Since the behavior of cytokines in this monkey model was similar to those noted in DIC in humans, this model will be useful for evaluating the efficacy of anti-DIC drugs. In addition, this model will also be useful for assessing the risk of cytokine storm development, which is a serious adverse effect of certain types of antibody drugs and CAR-T cell-based therapies.

著者

Kazunori Fujimoto Hiroyuki Kishino Kazuyuki Hashimoto Kyoko Watanabe Takashi Yamoto Kazuhiko Mori

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.6, pp.339-347, 2020 (Released:2020-06-04)

参考文献数

23

被引用文献数

6

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The metabolomic profiles of rat primary hepatocytes following treatment with rotenone, FCCP, or (+)-usnic acid were determined using liquid chromatography-mass spectrometry/mass spectrometry and gas chromatography-mass spectrometry. Significant and similar changes in the levels of 283 biochemical metabolites were associated with the three treatments compared with solvent control samples. Overall, the three treatments generated similar global biochemical profiles, with some minor differences associated with rotenone treatment. All three treatments resulted in a shift in energy metabolism as demonstrated by decreased glycogen stores and glycolysis. A reduced antioxidant response was detected in cells following all treatments. In addition, bile acid biosynthesis decreased as a potential consequence of increased oxidative stress by all three treatments. Conversely, rotenone treatment induced a number of changes after 1 hr, which were not detected in FCCP- or (+)-usnic acid-treated samples; these changes were not sustained over time and included increased NAD+ salvage and lysine degradation. In conclusion, these biochemical profiles could provide new insights into the mechanism(s) of mitochondrial toxicity.

著者

Nobuo Aikawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.4, pp.187-199, 2020 (Released:2020-04-01)

参考文献数

42

被引用文献数

19

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In vitro human induced pluripotent stem (iPS) cells testing (iPST) to assess developmental toxicity, e.g., the induction of malformation or dysfunction, was developed by modifying a mouse embryonic stem cell test (EST), a promising animal-free approach. The iPST evaluates the potential risks and types of drugs-induced developmental toxicity in humans by assessing three endpoints: the inhibitory effects of the drug on the cardiac differentiation of iPS cells and on the proliferation/survival of iPS cells and human fibroblasts. In the present study, the potential developmental toxicity of drugs was divided into three classes (1: non-developmentally toxic, 2: weakly developmentally toxic and 3: strongly developmentally toxic) according to the EST criteria. In addition, the type of developmental toxicity of drugs was grouped into three types (1: non-effective, 2: embryotoxic [inducing growth retardation/dysfunction]/deadly or 3: teratogenic [inducing malformation]/deadly) by comparing the three endpoints. The present study was intended to validate the clinical predictability of the iPST. The traditionally developmentally toxic drugs of aminopterin, methotrexate, all-trans-retinoic acid, thalidomide, tetracycline, lithium, phenytoin, 5-fluorouracil, warfarin and valproate were designated as class 2 or 3 according to the EST criteria, and their developmental toxicity was type 3. The non-developmentally toxic drugs of ascorbic acid, saccharin, isoniazid and penicillin G were designated as class 1, and ascorbic acid, saccharin and isoniazid were grouped as type 1 while penicillin G was type 2 but not teratogenic. These results suggest that the iPST is useful for predicting the human developmental toxicity of drug candidates in a preclinical setting.

著者

Hiroshi Iwasaki Masaki Wakamatsu Kazunari Sugihara Kyohei Kamio Satoshi Tsuji Junya Morita Yasuhiro Kurihara Tomoko Izumi Tomohiro Nishimoto Kohnosuke Kinoshita Yutaka Nakanishi Minoru Sasaki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.4, pp.201-218, 2020 (Released:2020-04-01)

参考文献数

32

被引用文献数

2

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TP0446131, developed as an antidepressant agent, was found to cause lenticular opacity in a 13-week repeated-dose study in dogs. Histopathologically, the lenticular opacity was observed as a degeneration of the lens fibers, characterized by irregularity in the ordered arrangement of the fibers which is necessary to maintain the transparency of the lens, and was considered to manifest clinically as cataract. To evaluate the development mechanism of the lenticular opacity, the chemical constituents of the lens, which is known to be associated with the development of cataract, were examined. The results of liquid chromatography-tandem mass spectrometry analysis revealed an increase in the amplitudes of 3 unknown peaks in a dose- and time-dependent manner in the lens, with no remarkable changes in the other chemical components tested. In addition, the content of cholesterol, alterations of which have been reported to be associated with cataract, remained unchanged. The mass spectral data and chromatographic behavior of the 3 peaks indicated that these peaks corresponded to sterol-related substances, and that one of them was 7-dehydrocholesterol, a precursor of cholesterol biosynthesis. This finding suggested that TP0446131 exerts some effects on the cholesterol biosynthesis pathway, which could be involved in the development of the cataracts. Furthermore, increases in the levels of these sterol-related substances were also detected in the serum, and were, in fact, noted prior to the onset of the cataract, suggesting the possibility that these substances in the serum could be used as potential safety biomarkers for predicting the onset of cataract induced by TP0446131.

著者

Tomoaki Tochitani Akihito Yamashita Izumi Matsumoto Mami Kouchi Yuta Fujii Toru Yamada Izuru Miyawaki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.9, pp.575-584, 2019 (Released:2019-09-02)

参考文献数

26

被引用文献数

2

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The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.

著者

Zaher A. Radi K. Nasir Khan

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.6, pp.373-391, 2019 (Released:2019-06-04)

参考文献数

184

被引用文献数

38

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Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic class in clinical medicine. These are sub-divided based on their selectivity for inhibition of cyclooxygenase (COX) isoforms (COX-1 and COX-2) into: (1) non-selective (ns-NSAIDs), and (2) selective NSAIDs (s-NSAIDs) with preferential inhibition of COX-2 isozyme. The safety and pathophysiology of NSAIDs on the renal and cardiovascular systems have continued to evolve over the years following short- and long-term treatment in both preclinical models and humans. This review summarizes major learnings on cardiac and renal complications associated with pharmaceutical inhibition of COX-1 and COX-2 with focus on preclinical to clinical translatability of cardio-renal data.

著者

Naoya Hirata Shigeru Yamada Yuko Sekino Yasunari Kanda

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.42, no.2, pp.193-204, 2017-04-01 (Released:2017-03-17)

参考文献数

45

被引用文献数

7 26

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Epidemiological studies suggest that lung cancer, which is a major cause of cancer death, has a critical association with cigarette smoking. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoke is a major risk factor for carcinogenesis. However, the mechanisms by which NNK promotes cancer development have not been fully elucidated. Growing evidence suggests that lung cancer originates from cancer stem cells (CSCs), which are a minor population of lung cancer cells. In the present study, we investigated the effects of NNK on the CSCs in A549 human lung cancer cells using flow cytometry with aldehyde dehydrogenase (ALDH), a functional marker of CSCs. We found that NNK increased the proportion of ALDH-positive cells in a dose-dependent manner. A Wnt inhibitor PNU74654 reduced NNK-induced expression levels of Wnt target gene Dkk1 and increase in ALDH-positive cells. We next examined the signaling pathway that mediates the NNK-induced increase in ALDH-positive cells via Wnt signaling. DCF assay revealed that NNK induced reactive oxygen species (ROS) production. The ROS scavenger N-acetylcysteine (NAC) inhibited the NNK-induced Wnt activation and increase in ALDH-positive cells. These data suggest that NNK-induced ROS activate the Wnt signaling pathway in A549 cells. These findings would provide new insights into the role of NNK in the lung CSCs.

著者

Hidetoshi SHINDOH Akira KAWASHIMA Nobuyuki SHISHIDO Kounosuke NAKANO Kazuko KOBAYASHI Ikuo HORII

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.31, no.3, pp.265-285, 2006 (Released:2006-09-08)

参考文献数

30

被引用文献数

5 15

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Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 μg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 μg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 μg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 μg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.

著者

竹本 稔 松尾 弘也 小黒 元春 河内 泰英

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.19, no.SupplementII, pp.249-262, 1994-10-15 (Released:2008-02-21)

参考文献数

10

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The antigenicity tests of Tazobactam/piperacillin (TAZ/PIPC), tazobactam (TAZ: β-lactamase inhibitor) and piperacillin (PIPC: penicillin antibiotic) were performed in mice and guinea pigs. The following results were obtained. 1. TAZ/PIPC, TAZ or PIPC had no immunogenicity and allergenicity in either passive cutaneous anaphylaxis (PCA) test using BALB/c and C3H/He mice or in PCA test using guinea pigs. 2. Guinea pigs sensitized with TAZ/PIPC, TAZ or PIPC showed no anaphylactic symptons in active systemic anaphylaxis (ASA) test. 3. Guinea pig PCA tests using protein conjugates as sensitizing and challenging antigens showed positive reactions. Immunological cross-reactivity tests were performed by using these conjugates in guinea pig PCA reaction. Results showed that TAZ/PIPC and PIPC cross-reacted with penicillin G (PCG) and ampicillin (ABPC), but not with cephalothin (CET) and cephmetazol (CMZ). TAZ did not cross-react with PCG, ABPC, CET or CMZ. 4. From the results of the passive hemagglutination (PHA) test, no antibody against TAZ/PIPC, TAZ or PIPC was detected. 5. In direct Coombs' test using human blood, TAZ/PIPC, TAZ, PCG and CET showed positive reactions at 20∼80, 5∼20, 80 and 10∼20 mg/ml, respectively. 6. The results of a test on in vitro covalent binding activity with human serum albumin indicated that the order of binding potency was CET>CMZ>ABPC>PCG=PIPC>TAZ under the physiological condition (pH 7.2∼7.4), and was CMZ>CET>ABPC>PIPC>TAZ>PCG under the alkaline condition (pH 10.0∼10.5), respectively.

著者

大内田 昭信 谷口 明美 河内 泰英 前田 泰宏 樫原 昭裕 大前 重男

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.19, no.SupplementII, pp.263-280, 1994-10-15 (Released:2008-02-21)

参考文献数

17

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TAZ/PIPCの安全性試験の一環として, tazobactam(TAZ), piperacillin(PIPC)およびそれらの配合剤(TAZ/PIPC)について変異原性の有無を検討するために, 細菌を用いた復帰突然変異試験, 培養細胞を用いた染色体異常試験およびICR雄マウスを用いた小核試験を実施した。1. TAZ, PIPCおよびTAZ/PIPCの復帰突然変異試験ではS. typhimurium TA100, TA98, TA1535, TA1537, およびE. coli WP2uvrAを用いて, 抗菌作用が認められる用量を最高に以下公比2~2.5で減じた7段階の用量で実施した。TAZ, PIPCおよびTAZ/PIPCは代謝活性化の有無にかかわらず, いずれの菌株も溶媒対照群と比較して復帰変異コロニー数の用量に依存した明らかな増加は認められなかった。2. TAZ, PIPCおよびTAZ/PIPCの染色体異常試験では培養細胞CHLを用い, 直接法および代謝活性化法の両法において10mMを最高に以下公比2で減じた3~4用量の処理群について染色体標本を観察した。TAZ, PIPCおよびTAZ/PIPCは直接法および代謝活性化法のいずれにおいても染色体の構造異常あるいは数的異常の出現頻度は0~3.0%で, 溶媒対照群と差がなかった。3. TAZおよびTAZ/PIPCの小核試験では625, 1250, 2500, 5000 mg/kgの投与用量で, PIPCでは625, 1250, 2500 mg/kgの投与用量で実施した。TAZ, PIPCおよびTAZ/PIPCにおけるMNPCEの出現率はそれぞれ0.02~0.17%, 0.02~0.1%および0.03~0.07%であり, 用量依存性はみられなかった。また, 背景データを用いた判定法でも陰性であった。4. 上記の結果より, TAZ, PIPCおよびTAZ/PIPCには変異原性は認められなかった。

著者

林 泰司 矢田 英昭 穴井 真紀子 馬野 高昭 河津 孝二 穴井 俊二 梶原 利彦 山崎 寛治

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.19, no.SupplementII, pp.145-153, 1994-10-15 (Released:2008-02-21)

参考文献数

7

被引用文献数

1

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TAZ/PIPCおよびTAZのマウス, ラットおよびイヌにおける単回投与毒性を検討し, 以下の結果を得た。1. マウスおよびラッ卜ではTAZ/PIPC, TAZともすべての投与経路において軟便がみられ, 皮下, 腹腔内および静脈内投与では自発運動の低下あるいは呼吸数の減少などもみられた。TAZ/PIPCの静脈内投与の死亡例では, マウスで振戦, ラットで間代性痙攣を呈し死亡し, 剖検では肺の充血, 出血または水腫, 消化管の出血などがみられた。また, TAZ/PIPCを投与した生存例の一部に脾の腫大がみられた。2. イヌではTAZ/PIPC投与により嘔吐がみられ, TAZ投与により嘔叶, 呼吸異常, 軟梗あるいは下痢便などがみられた。3. マウスおよびラットでは, 本剤の刺激性による投与部位の脱毛(皮下投与), 尾部の壊死(静脈内投与), イヌでは投与前肢の跛行がみられ, 剖検では壊死, 出血, 腹膜炎(腹腔内投与)などがみられた。4. TAZ/PIPCでは, マウスおよびラットの経口, 皮下および腹腔内投与でのLD50値は, 5,000mg/kg 以上(雌雄)であった。静脈内投与ではマウスが5,000mg/kg以上(雄), 4,565mg/kg(雌), ラットが3,157mg/kg(雄), 3,992mg/kg(雌), イヌが5,000 mg/kg以上であった。TAZでは, マウスおよびラット(雌雄)の経口, 皮下, 腹腔内, 静脈内投与およびイヌの静脈内投与ではLD50値は5,000 mg/kg以上であった。

著者

Xiaoting Jin Bin Xue Qunfang Zhou Ruijun Su Zhuoyu Li

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.43, no.2, pp.101-111, 2018 (Released:2018-02-26)

参考文献数

36

被引用文献数

70

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Mitochondria can be used as important biomarkers of pollutants on human health, and fine particulate matter (PM2.5) has been documented to cause respiratory damage. However, current studies about the relationship between PM2.5 and mitochondria in respiratory tract are limited and warrant further detailed investigations. Hence, the study was aimed to evaluate effects of PM2.5 on mitochondrial structure, investigate the link between PM2.5-induced mitochondrial disorder and respiratory damage, and delineate the possible mechanisms using both in vitro and in vivo models. PM2.5 exposure resulted in damage of mitochondrial structure, including mitochondrial dynamic, DNA biogenesis and morphological alteration 16HBE cells. Furthermore, PM2.5 elevated ROS formation. However, DPI and NAC (inhibitor of ROS) in supplement restored PM2.5-induced mitochondrial disorder. PM2.5 also contributed to the 16HBE cells apoptosis via mitochondrial pathway. Additionally, the results coincided with the in vivo data which were obtained from bronchial tissues of SD rats exposed to PM2.5 for 30 days. Collectively, this study uncovers that PM2.5 leads to the disorder of mitochondrial structure via ROS generation, and then results in respiratory damage. It provides further understanding about the detrimental effect of PM2.5 on respiratory damage, and reveals a mechanistic basis for preventing outcomes in polluted environments.

著者

Hongquan Zhu

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.42, no.2, pp.233-240, 2017-04-01 (Released:2017-03-17)

参考文献数

23

---

この論文は撤回されました。

著者

Horii Ikuo

出版者

The Japanese Society of Toxicology

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.35, no.4, pp.425-435, 2010-08-01

被引用文献数

1 3

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The theory of Darwinian Medicine linked to an extension of Darwin's evolutionary theory is based on the approach from the aspect of "why we become ill?". This theory enables us to understand the relationship between humans and diseases by thinking from evolutional perspective, shows an important help for preventive medicine, and is meaningful to consider the future human healthcare. Toxicology has been defined as a research of adverse effect of xenobiotic substances backed up by diverse-sciences. Toxic effects are basically responses to xenobiotic substances, and expressed as triggering or additional accelerating adverse effects toward abnormal condition. Toxic effects, biological adverse responses, are interpreted as protective responses of living body, and the adverse effects caused by drugs are also considered to be protective responses. This logic can be translated as "Darwinian Toxicology" corresponding to "Darwinian Medicine", replying to "why we get into toxic condition by xenobiotics exposure". This paper refers to the meaning of toxic effects based on mechanisms underlying and comprehensive drug safety evaluation from Darwinian Medicine perspectives.

著者

Kanae Umeda Yaichiro Kotake Masatsugu Miyara Keishi Ishida Seigo Sanoh Shigeru Ohta

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.2, pp.255-264, 2016-04-01 (Released:2016-03-10)

参考文献数

46

被引用文献数

12 18

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GluR2, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors. Treatment of cultured rat cortical neurons with 1 or 10 µM methoxychlor and fenvalerate for 9 days selectively decreased GluR2 protein expression; the expression of other AMPA receptor subunits GluR1, GluR3, and GluR4 did not change under the same conditions. Importantly, the decreases in GluR2 protein expression were also observed on the cell surface membrane where AMPA receptors typically function. In addition, both chemicals decreased neuronal viability, which was blocked by pretreatment with 1-naphtylacetylspermine, an antagonist of GluR2-lacking AMPA receptors, and MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. These results suggest that long-term exposure to methoxychlor and fenvalerate decreases GluR2 protein expression, leading to neuronal death via overactivation of GluR2-lacking AMPA and NMDA receptors.

著者

Kazuhiko Imaizumi Shogo Sato Mari Kumazawa Natsuko Arai Shoko Aritoshi Shunta Akimoto Yuko Sakakibara Yu Kawashima Kaoru Tachiyashiki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.36, no.1, pp.109-116, 2011-02-01 (Released:2011-02-01)

参考文献数

23

被引用文献数

13 16

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Red peppers are used as a spice for enhancing the palatability of foods. Two major capsaicinoids, dihydrocapsaicin (DHC) and capsaicin (CAP) are responsible for up to 90% of the total pungency of pepper fruits. These capsaicinoids are known to enhance energy metabolism and thermogenesis. However, there is a little information on the effects of capsaicinoids on the lipolysis and carbohydrate metabolism. We studied the effects of DHC and CAP on plasma glucose, free fatty acid (FFA) and glycerol concentrations in rats. Male six-week-old Sprague Dawley rats were divided into the DHC, CAP and control groups. Each capsaicinoid (dose = 3 mg/kg BW/day) was subcutaneously administered to rats for 10 days. DHC increased markedly plasma glucose, FFA and glycerol concentrations on day 1-10 by 14-35%, 61-103% and 108-174%, respectively, as compared with those of the control group. CAP increased relatively plasma glucose concentrations on day 1-3 by 15-17%, as compared with the control group. However, there were no significant differences in plasma glucose concentrations on day 7-10 among three groups. On the contrary, CAP did not change plasma FFA and glycerol concentrations on day 1-3. However, CAP increased markedly plasma FFA and glycerol concentrations on day 7-10 by 54-89% and 92-98%, respectively, as compared with the control group. DHC and CAP did not change the weights of white (perirenal and periepididymal) and brown (interscapular) adipose tissues. In conclusion, the effects of capsaicinoids on plasma glucose, FFA and glycerol concentrations were relatively higher in the DHC than in the CAP, and capsaicinoids did not change the weight of white and brown adipose tissues.

著者

Bao-qiu Li Xin Dong Shi-hong Fang Gui-qin Yang Ji-you Gao Jian-xin Zhang Fang-min Gu Hua Zhao

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.35, no.3, pp.279-286, 2010-06-01 (Released:2010-06-01)

参考文献数

23

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Aim: Non-cell corynebacterium parvum product (NCPP) is a new preparation of corynebacterium parvum (CP), an immunomodulator that displays anticancer activities. It is prepared by nanotechnology and is intended to minimize the side effects of CP. The aim of the present study was to evaluate the immunogenicity and systemic toxicity of NCPP compared with CP in animals. Methods: 30 monkeys were randomly divided into 5 groups and given CP (3 mg/monkey), three doses of NCPP (9, 3, 1 mg/monkey) and 0.9% normal saline (NS, 4 ml/monkey) individually by intramuscular injection twice a week for 13 weeks. The immunogenicity and systemic toxicity of NCPP and CP were compared. Results: NCCP and CP caused histopathological changes in the liver, spleen and kidney, but pathologic changes in NCCP-treated groups were slighter than that in the CP group. Only 9 mg/monkey of NCPP caused the similar damage as the CP in intensity. Deposition of immune complexes in the glomerular basement membrane was observed only in the CP group. ELISA detection showed that the anti-CP antibody was at a high level, while the anti-NCPP antibody was at low level and disappeared during the recovery period. Conclusion: Our study has led to the view that NCPP is safer than CP.

著者

Masaaki Miyazawa Yuichi Ito Nanae Kosaka Yuko Nukada Hitoshi Sakaguchi Hiroyuki Suzuki Naohiro Nishiyama

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.33, no.1, pp.71-83, 2008 (Released:2008-02-26)

参考文献数

37

被引用文献数

19 24 18

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Dendritic cells (DCs), including Langerhans cells (LCs), play a critical role in the induction phase of allergic contact hypersensitivity. Following exposure to chemical allergens in the skin, LCs undergo a maturation process leading to the up-regulation of expression of co-stimulatory molecules, such as CD86, CD54 and CD40. Our previous study revealed that chemical allergens induce phenotype alterations (e.g., CD86, CD54 and CD40) and cytokine production (TNF-α and IL-8) in THP-1 cells that possibly reflect the maturation of dendritic cells during skin sensitization. However, the physiological signals for phenotypic alterations by chemical allergens are still not fully understood. Therefore, in this study, we investigated the effect of TNF-α and extracellular ATP on THP-1 cell activation induced by chemical allergens. Kinetic studies revealed that TNF-α and IL-8 release occurred in a time-dependent manner with release of two cytokines beginning at 3 hr post-exposure to well-known haptens, DNCB and NiSO4. While recombinant human TNF-α augmented CD54 and CD40 expression in a dose-dependent manner, rhTNF-α did not increase CD86 expression. Furthermore, neutralization of TNF-α activity strongly inhibited CD54 and CD40 expression induced by allergens. On the contrary, extracellular ATP induced the up-regulation of both CD86 and CD54 expression. In the presence of the P2 receptor antagonist suramin, the up-regulation of CD86 and CD54 expression by allergens was in part suppressed. Therefore, we postulate that not only TNF-α but also extracellular ATP may contribute to cell activation following allergen stimulation, which might reflect the mechanism by which DCs respond to allergens.

著者

Atsuya Takagi Akihiko Hirose Tetsuji Nishimura Nobutaka Fukumori Akio Ogata Norio Ohashi Satoshi Kitajima Jun Kanno

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.33, no.1, pp.105-116, 2008 (Released:2008-02-26)

参考文献数

22

被引用文献数

428 655

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Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/ carcinogenic properties, especially of their long-term biodurability, are fully assessed.

著者

Jun SATO Yasuhito YAMAMOTO Tsuneaki NAKAMURA Shigeru ISHIDA Yutaka TAKAGI

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.30, no.4, pp.339-347, 2005 (Released:2006-01-11)

参考文献数

14

被引用文献数

3 3

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We evaluated the toxicity of tetradecanoic acid methyl ester sodium salt (C14-MES), a major component of fabric detergents, following the test guidelines of the Organization for Economic Cooperation and Development. The rat acute oral LD50 was 1,000 mg/kg in males and 500 mg/kg in females. Applying the combined repeated dose and reproductive/developmental toxicity screening test (ReproTox), we exposed groups of Crj:CD (SD) IGS rats to C14-MES in the diet at concentrations of 0, 0.3, 0.6, or 1.2%. We observed decreases in fibrinogen levels and longer prothrombin time at the 1.2% treated level in females and decreases in serum triglyceride levels in both sexes at the 0.6% and 1.2% treatment levels, but the effects were not clinically significant. The no-observed-effect-level (NOEL) for repeated dose toxicity was 0.3% (175 mg/kg body weight/day for males, 249 for females). The NOEL for reproduction/developmental toxicity was 1.2% (740 mg/kg for males, 1039 for females). C14-MES was negative in the reverse gene mutation assay and the chromosomal aberration test and did not induce skin sensitization in the guinea pig maximization test. These data confirm that C14-MES is of low hazard potential.