著者

村上 善紀 Fujii Hisako Ichimura Akitoshi MURATA Akiko YAMASHITA Noriaki TAKAGI Hidetoshi TAUCHI Kiyonori

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.23, pp.11-29, 1998-05-09

参考文献数

19

被引用文献数

1

---

To clarify whether levofolinate calcium (1-LV) enhances 5-fluorouracil (5-FU) toxicity, a 4-week toxicity study of 5-FU (10 mg/kg/day) in combination with 1-LV (6, 20 or 60 mg/kg/day) was conducted in rats. In the 5-FU alone group, a decrease in body weight gain, food consumption, RBC parameter and WBC counts were detected. Histopathologically, lymphoid depletion of lymphatic organs, hematopoiesis enhancement of the spleen and myelosuppression were observed. In the group for which 5-FU was combined with 1-LV, the RBC counts decreased, extramedullary hematopoiesis increased and the suppression of lymphatic organs was enhanced. Changes in the lymphatic organs were observed at 20 mg/kg/day of 1-LV and above. In monitoring of blood drug concentrations of 1-LV, 5-methyl tetrahydrofolic acid, a metabolite of 1-LV, and 5-FU after the 1st and 14th dosings, there was no apparent difference between 5-FU alone and 5-FU combined with 1-LV in C_<max> and AUC_<0-∞>. The potentiation induced by 1-LV in the toxicity of 5-FU appeared to be mainly immuno-suppression and myelosuppression, which were related to the anti-tumor activity of 5-FU. Plasma concentrations of 5-FU and 1-LV in this study overwhelmed the concentrations that enhancement of thymidylate synthetase (TS) inhibition due to 5-FU was observed by addition of 1-LV in vitro. Therefore toxic potentiation of 5-FU due to simultaneous 1-LV dosing is presumed to be concerned with an increased ternary complex (FdUMP-TS-5, 10-methylenetetrahydrofolate) formation and a greater extent of TS inhibition.

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

---

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

---

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

北垣 忠温 鈴木 登志郎 小池 嘉秀 小野 正博 白川 清美 永田 充宏 小西 良士

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.21, pp.325-343, 1996-07-05

参考文献数

13

被引用文献数

2

---

MC903の安全性を検討するため,0,0.4,2および10 μg/kg/dayをSlc:SD系雌雄ラットの頸背部皮下に26週間投与した。さらに,2および10 μg/kg/day群について,5週間の回復試験を実施し,以下の結果を得た。1. 死亡例は試験期間を通して,各群の雌雄に認めなかった。一般状態では10 μg/kg群の雄に眼球表面の一部白濁の発生頻度が増加した。2. 体重および摂餌量は,試験期間を通して,雌雄とも対照群とほぼ同様に推移した。10 μg/kg群の雌雄に,摂水量の増加ないし増加傾向を認めた。3. 投与期間終了時に,眼科学的検査で,10 μg/kg群の雌雄に角膜表面の一部混濁の発生頻度が増加した。尿検査で,2 μg/kg群以上の雄に尿中カルシウム排泄量の増加,10 μg/kg群の雄に尿中ナトリウム・クロライド・無機リン排泄量の増加,雌に尿量の減少,雌雄にpHの低下を認めた。血液化学的検査で,2 μg/kg群の雄および10 μg/kg群の雌雄に血中カルシウム濃度の増加,10 μg/kg群の雄に血中ALP活性の上昇を認めた。器官重量で,2 μg/kg群以上の雄に腎臓絶対重量・相対重量の増加,10 μg/kg群の雌雄に副腎絶対重量・相対重量の増加を認めた。病理組織学的検査で,2 μg/kg群以上の雄に角膜・腎臓の鉱質化の発生頻度の増加を認めた。電子顕微鏡検査で,10 μg/kg群の雌雄の腎臓に遠位尿細管上皮細胞の滑面小胞体を主とした小胞体の拡張を認めた。4. 5週間の休薬により,眼球表面の一部白濁,角膜表面の一部混濁および角膜・腎臓の鉱質化は回復しなかった。その他の変化は回復または軽減し,可逆性の変化であった。5. 以上の結果,本試験条件下におけるMC903の無毒性量は,雌雄とも0.4 μg/kg/dayと推定した。

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

---

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

---

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

---

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

---

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

Machida Kazuhiko Suemizu Hiroshi Kawai Kenji Ishikawa Tsuyoshi Sawada Rumi Ohnishi Yasuyuki Tsuchiya Toshie

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.34, no.1, pp.123-127, 2009-02-01

参考文献数

21

被引用文献数

2 35

---

The purpose of tumorigenicity testing, as applied not only to cell substrates used for viral vaccine manufacture but also stem cells used for cell-based therapy, is to discriminate between cells that have the capacity to form tumors and cells that do not. Therefore, tumorigenicity testing is essential in assessing the safety of these biological materials. Recently developed NOD/Shi-scid IL2Rg^<null> (NOG) mice have been shown to be superior to NOD/Shi-scid (SCID) mice for xenotransplantation of both normal and cancerous cells. To select a suitable mouse strain as a xenogenic host for tumorigenicity testing, we compared the susceptibility of NOG (T, B, and NK cell-defective), SLID (T and B cell-defective), and the traditionally used nude (T cell-defective) mice to tumor formation from xenotransplanted HeLa S3 cells. When 10^4 HeLa S3 cells were subcutaneously inoculated into the flanks of these mice, the tumor incidence on day 22 was 10/10 (100%) in NOG, 2/10 (20%) in SCID, and 0/10 (0%) in nude mice. The subcutaneous tumors formed reproducibly and semiquantitatively in a dose-dependent manner. Unexpectedly, half of the NOG mice (5/10) that had been inoculated with a mere 10^1 HeLa S3 cells formed progressively growing subcutaneous tumors on day 78. We confirmed that the engrafted tumors originated from inoculated HeLa S3 cells by immunohistochemical staining with anti-HLA antibodies. These data suggest that NOG mice may be the best choice as a suitable strain for testing tumorigenicity.

著者

Kanako Noritake Toshihiko Aki Moe Kimura Takeshi Funakoshi Kana Unuma Koichi Uemura

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.42, no.5, pp.545-551, 2017-10-01 (Released:2017-09-13)

参考文献数

31

被引用文献数

2

---

We reported previously that when mouse atrium-derived HL-1 cardiomyocytes undergo apoptosis upon exposure to 2% ethanol, the cellular cytoskeleton is severely disrupted and the anti-apoptotic transcriptional co-activator Yes-associated protein (YAP) is inactivated. Consistent with our previous observations, the expression of connective tissue growth factor (CTGF), an anti-apoptotic growth factor and a target of YAP, decreases in a time-dependent manner during exposure to 2% ethanol. The restoration of YAP activation rescues the cells from apoptosis: both the retrovirus-mediated expression of constitutively active YAP and the stabilization of the actomyosin cytoskeleton by jasplakinolide prevent cell death. In contrast, YAP inhibitors have no effect on cell death, confirming the inactivation of YAP in ethanol-exposed cells. Thus, a decrease in actin tension and YAP inactivation should be crucially involved in the cytotoxicity of ethanol on HL-1 cardiomyocytes.

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

菱田 尚樹 久世 博 山村 高章 野口 通重 川合 是彰 堀 正樹

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.22, pp.327-334, 1997-11-13

参考文献数

7

被引用文献数

1

---

新規TRH誘導体であるタルチレリン水和物(TA-0910)の急性毒性試験を, マウスおよびラットにおいて経口, 静脈内および皮下投与で, イヌにおいでは経口および静脈内投与で実施した。マウスおよびラットの経口および皮下投与では死亡は認められず, LD_<50%gt;値は全て5000 mg/kg以上となった。また, イヌの経口投与でも死亡は認められず, 最小致死量は2000 mg/kg以上となった。一方, マウスの静脈内投与では, 700 mg/kg以上で死亡はみられたものの, LD_<50%gt;値は雌雄とも2000 mg/kg以上, ラットでは, 640 mg/kg以上で死亡がみられ, 雄で799 mg/kg, 雌で946 mg/kgとなった。死亡は全て投与中ないし投与直後であった。イヌの静脈内投与では, 最高用量の1000 mg/kg投与で死亡はみられなかったが, 500 mg/kg投与の雌1例が投与翌日に死亡し, 雌の最小致死量は500mg/kgとなった。一般状態の観察では, マウスおよびラットの全ての投与経路に共通して, TA-0910の中枢神経賦活作用を反映する, 運動性充進, 振せん, 挙尾反応等が認められ, さらにラットの各経路ではwet dog shakingが認められた。イヌの経口投与では, 嘔吐, 興奮症状が, 静脈内投与では, 投与中の興奮, 投与後の鎮静等が認められ, さらに両経路に共通して, 流涎および一過性の心拍数の増加等が認められた。また, 血液生化学検査では, 蛋白, 糖, 脂質, 血清酵素に一過性の変動がみられた。剖検では, マウス, ラットおよびイヌとも, 被験物質起因の異常はみられなかった。

著者

山田 英之 福島 直 小栗 一太

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.23, pp.App.161-App.170, 1998-11-26

参考文献数

39

著者

Shuji Tsuda

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.Special, pp.SP27-SP36, 2016-12-20 (Released:2016-12-20)

参考文献数

57

被引用文献数

67

---

Perfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are representatives of PFASs. Recently, the U.S. Environmental Protection Agency (US EPA) set the health advisory level as 70 parts per trillion for lifetime exposure to PFOS and PFOA from drinking water, based on the EPA’s 2016 Health Effects Support Documents. Then, a monograph on PFOA was made available online by the International Agency for Research on Cancer, where the agency classified PFOA as “possibly carcinogenic to humans” (Group 2B). The distinction between PFOS and PFOA, however, may not be easily understood from the above documents. This paper discussed differential toxicity between PFOS and PFOA focusing on neurotoxicity, developmental toxicity and carcinogenicity, mainly based on these documents. The conclusions are as follows: Further mechanistic studies may be necessary for ultrasonic-induced PFOS-specific neurotoxicity. To support the hypothesis for PFOS-specific neonatal death that PFOS interacts directly with components of natural lung surfactant, in vivo studies to relate the physicochemical effects to lung collapse may be required. PFOA-induced DNA damage secondary to oxidative stress may develop to mutagenicity under the condition where PFOA-induced apoptosis is not sufficient to remove the damaged cells. A study to find whether PFOA induces apoptosis in normal human cells may contribute to assessment of human carcinogenicity. Studies for new targets such as hepatocyte nuclear factor 4α (HNF4α) may help clarify the underlying mechanism for PFOA-induced carcinogenicity.

著者

Ikuo Horii

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.Special, pp.SP49-SP67, 2016-12-31 (Released:2017-03-01)

参考文献数

65

被引用文献数

7

---

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as “biological responses to foreign substances.” This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of “on-target” or “off-target”, and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of “how can multidisciplinary toxicology contribute to innovative drug discovery and development?” And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision medicine are to be addressed for the new aspect of efficacy and safety evaluation.

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

---

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

Xin Cao Yuji Nakamura Takeshi Wada Hiroko Izumi-Nakaseko Kentaro Ando Atsushi Sugiyama

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.3, pp.439-447, 2016-06-01 (Released:2016-05-17)

参考文献数

21

被引用文献数

14

---

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca2+ channel but inhibit Na+ and K+ channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.

著者

Biswadev BISHAYI Subhashree ROYCHOWDHURY Soumya GHOSH Mahuya SENGUPTA

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.27, no.3, pp.139-146, 2002 (Released:2003-01-31)

参考文献数

25

被引用文献数

30 89

---

Effect of Tinospora cordifolia extract on modulation of hepatoprotective and immunostimulatory functions in carbon tetrachloride (CCl4) intoxicated mature rats is reported here. Administration of CCl4 (0.7 ml/kg body weight for 7 days) produces damage in the liver as evident by estimation of enzymes such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transminase (SGPT) and alkaline phosphatase (ALP) as well as serum bilirubin level. CCl4 administration also causes immunosuppressive effects as indicated by phagocytic capacity, chemotactic migration and cell adhesiveness of rat peritoneal macrophages. However, treatment with T. cordifolia extract (100 mg/kg body weight for 15 days) in CCl4 intoxicated rats was found to protect the liver, as indicated by enzyme level in serum. A significant reduction in serum levels of SGOT, SGPT, ALP, bilirubin were observed following T. cordifolia treatment during CCl4 intoxication. Treatment with T. cordifolia extract also deleted the immunosuppressive effect of CCl4, since a significant increment in the functional capacities of rat peritoneal macrophages (PMφ) was observed following T. cordifolia treatment. The results of our experiment suggest that treatment by T. cordifolia extract may be the critical remedy for the adverse effect of CCl4 in liver function as well as immune functions.

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

---

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

Kyoichi ASANO Masaya YAMANO Kiyoshi HARUYAMA Etuo IKAWA Kazumasa NAKANO Masayasu KURONO Osamu WADA

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.19, no.SupplementII, pp.131-143, 1994-10-15 (Released:2008-02-21)

参考文献数

15

被引用文献数

3 4 6

---

A histopathological study was performed to examine the influence of propagermanium and germanium dioxide (GeO2) on chemically induced renal lesions in rats. Animals were treated with adriamycin or mercuric chloride to induce glomerular or proximal tubular damage, and then given drinking water containing propagermanium (480 or 2, 400 ppm solution) or GeO2 (300 or 1, 500 ppm solution: equivalent to propagermanium in terms of germanium contents). The distal tubular epithelium after 8 weeks dosage with the 1, 500 ppm solution of GeO2 was characterized by vacuolization and deposits of PAS-positive material not only in adriamycin-treated rats, but also in normal rats. In contrast, propagermanium administration was not associated with any alteration in the changes induced by adriamycin or mercuric chloride. We previously clarified that propagermanium had no biochemical influence on the renal function of these renal injured rats. The histological demonstration that this compound does not exert renal toxicity, even when given at a high dosage to renal injured rats, further indicates that it would not exacerbate renal dysfunction already present. This confirms that propagermanium may be a safe compound for use in individuals with compromised kidneys.