著者

Guojun Yin Liping Cao Jinliang Du Rui Jia Takio Kitazawa Akira Kubota Hiroki Teraoka

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.4, pp.455-459, 2017-08-01 (Released:2017-07-13)

参考文献数

16

被引用文献数

12

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Fish hepatobiliary syndrome, characterized by hepatomegaly and fatty liver, has been frequently reported in many cultured fish species and has caused a dramatic economic loss in China. Glucocorticoids are thought to be important non-nutritional factors for hepatomegaly and fatty liver development. In the present study, a dexamethasone-induced zebrafish model of fatty liver and hepatomegaly was established, and the role of glucocorticoid receptor (GR) in the development of hepatomegaly and fatty liver was investigated using developing zebrafish. Exposure of larval zebrafish at 5 days post fertilization (dpf) to dexamethasone for 24 hr caused significant increases of liver size and number of fish with hepatic steatosis at 6 dpf. The increase of liver size caused by dexamethasone was significantly reversed by treatment with RU486, a GR antagonist, and by gene knock-down with a morpholino against the GR. The dexamethasone-induced hepatic steatosis was also inhibited by treatment with RU486. Overall, the results highlight larval zebrafish as a useful model for stress-induced liver failure.

著者

Takashi Ashino Kanae Hakukawa Yuka Itoh Satoshi Numazawa

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.39, no.6, pp.815-820, 2014-12-01 (Released:2014-11-06)

参考文献数

23

被引用文献数

12

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Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity.

著者

中野 茂樹 桑田 雅彦 長谷川 浩之 入村 兼司 丸伝 章 森田 健一

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.14, pp.13-59, 1989-10-31

被引用文献数

3 5

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ラットにP-4を2, 10, 50および150mg/kg/dayの投与量で13週間経口投与し, その亜急性毒性ならびに回復性を検討し, 以下の知見を得た. 1. 一般状態の観察では, 50mg/kg/day以上の雌雄各群で投薬後一過性の流涎と主に雌で尿による下腹部の汚染が観察された. その他に重篤な中毒症状はみられず, P-4投与によると思われる死亡例もなかった. 2. 体重は, 雄の50mg/kg/day以上, 雌の150mg/kg/dayの群で増加抑制がみられたが, 摂餌量に著しい変動はなかった. 摂水量は雌雄とも50mg/kg/day以上群で, 投薬初期より明らかな増加を示した. 3. 尿検査では, 50mg/kg/day以上の雌雄各群で尿量の増加, 浸透圧の低下, 蛋白およびウロビリノーゲンの陰性化, さらに電解質排泄量の軽度増加がみられた. 4. 血液学的検査では,150mg/kg/day群の雌雄に赤血球数の増加およびAPTTの短縮, さらに雄ではヘモグロビン量およびヘマトクリット値の増加, 白血球数の減少と雌ではフィブリノーゲン量の増加がいずれも軽度にみられた. 5. 血液生化学的検査では, 雄の50mg/kg/day以上および雌の150mg/kg/dayの群に中性脂肪の減少とγ-GTPおよびAlP活性, および尿素窒素の増加がみられた. さらに雄では総および遊離コレステロール, およびリン脂質が減少し, 雌では総コレステロールの増加およびコリンエステラーゼ活性の減少がみられた. 6. 病理学的検査では, 50mg/kg/day以上の雌雄各群に胸腺および脾臓の肉眼的萎縮がみられたが, 病理組織学的異常は認められなかった. 雄の50mg/kg/day以上および雌の150mg/kg/day群では肝臓重量または重量比が増加し, 病理組織学的検査で肝細胞の肥大および脂肪変性が観察された. 電子顕微鏡検査では, 同群でさらに肝細胞に著明な滑面小胞体の増殖を認めた. 腎臓では, 雄の10mg/kg/day以上, 雌の50mg/kg/day以上の群の近位尿細管上皮細胞内に好酸性の核内封入物を認めたが, その細胞質に腎障害像は全くみられなかった. 7. 回復試験では, P-4投与によるいずれの変化も回復ないし回復傾向を示し, 可逆性の変化であることが示唆された. 8. 無影響量は雄で2mg/kg/day, 雌で10mg/kg/day, 確実中毒量は雄で50mg/kg/day, 雌で150mg/kg/dayと推察された.

著者

Ken-ichi Wakabayashi Yoshimasa Kurata Tomoo Harada Yasushi Tamaki Naohiro Nishiyama Toshio Kasamatsu

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.37, no.4, pp.691-698, 2012-08-01 (Released:2012-08-01)

参考文献数

23

被引用文献数

10 22

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Glycidol fatty acid esters (GEs) have been identified as contaminants in refined edible oils. Although the possible release of glycidol (G) from GEs is a concern, little is known about the conversion of GEs to G in the human body. This study addressed the toxicokinetics of glycidol linoleate (GL) and G in male Crl:CD(SD) rats and cynomolgus monkeys. Equimolar amounts of GL (341 mg/kg) or G (75 mg/kg) were administered by gavage to each animal. G was found in both species after the G and GL administration, while plasma GL concentrations were below the lower limit of quantification (5 ng/ml) in both species. In rats, the administration of GL or G produced similar concentration-time profiles for G. In monkeys, the Cmax and AUC values after GL administration were significantly lower than those after G administration. The oral bioavailability of G in monkeys (34.3%) was remarkably lower than that in rats (68.8%) at 75 mg/kg G administration. In addition, plasma G concentrations after oral administration at three lower doses of GL or G were measured in both species. In monkeys, G was detected only at the highest dose of G. In contrast, the rats exhibited similar plasma G concentration-time profiles after GL or G administration with significantly higher G levels than those in monkeys. In conclusion, these results indicate that there are remarkable species differences in the toxicokinetics of GEs and G between rodents and primates, findings that should be considered when assessing the human risk of GEs.

著者

山添 康

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, no.2, 1996-05-25

著者

Masakazu Umezawa Hitoshi Tainaka Natsuko Kawashima Midori Shimizu Ken Takeda

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.37, no.6, pp.1247-1252, 2012-12-01 (Released:2012-12-01)

参考文献数

25

被引用文献数

34 40

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The production of man-made nanoparticles is increasing in nanotechnology, and health effect of nanomaterials is of concern. We previously reported that fetal exposure to titanium dioxide (TiO2) affects the brain of offspring during the perinatal period. The aim of this study was to extract candidate brain regions of interest using a specific group of Medical Subject Headings (MeSH) from a microarray dataset of the whole brain of mice prenatally exposed to TiO2 nanoparticle. After subcutaneous injection of TiO2 (total 0.4 mg) into pregnant mice on gestational days 6-15, brain tissues were collected from male fetuses on embryonic day 16 and from male pups on postnatal days 2, 7, 14 and 21. Gene expression changes were determined by microarray and analyzed with MeSH indicating brain regions. As a result, a total of twenty-one MeSH were significantly enriched from gene expression data. The results provide data to support the hypothesis that prenatal TiO2 exposure results in alteration to the cerebral cortex, olfactory bulb and some regions intimately related to dopamine systems of offspring mice. The genes associated with the striatum were differentially expressed during the perinatal period, and those associated with the regions related to dopamine neuron system and the prefrontal region were dysregulated in the later infantile period. The anatomical information gave us clues as to the mechanisms that underlie alteration of cerebral gene expression and phenotypes induced by fetal TiO2 exposure.

著者

Masaya Motohashi Michael F. Wempe Tomoko Mutou Yuya Okayama Norio Kansaku Hiroyuki Takahashi Masahiro Ikegami Masao Asari Shin Wakui

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.6, pp.R1, 2023 (Released:2023-06-06)

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Editor’s AnnouncementIn utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in ratsMasaya Motohashi, Michael F. Wempe, Tomoko Mutou, Yuya Okayama, Norio Kansaku, Hiroyuki Takahashi, Masahiro Ikegami, Masao Asari, Shin Wakui(The Journal of Toxicological Sciences, 41, 195-206, 2016) I have retracted the above paper as Editor-in-Chief of The Journal of Toxicological Sciences since I have serious concerns about it, primarily due to inappropriate authorship on a non-negligible scale.When it was brought to my attention that there was inappropriate authorship in this paper, I contacted the co-authors to confirm this point. I found out that the majority of them considered their listing as co-authors to be inappropriate. In addition, the majority agreed to the retraction of this paper.These facts raise concerns about the paper. From the standpoint of maintaining the integrity of the research community, I felt that such a paper should be retracted at once.Accordingly, I sent a summary of my concerns about the paper to the corresponding author, Dr. Shin Wakui. I also had an online interview with him to discuss this matter. I told Dr. Wakui that inappropriate authorship on a non-negligible scale is a serious problem that raises concerns about the paper.I prepared a draft of this Editor’s Announcement and sent it to Dr. Wakui for review prior to revision and release. Although he did not agree to the retraction, I have decided to take this action from the standpoint of maintaining the integrity of the research community.I coordinated my response to this issue with Dr. Akira Naganuma, Editor-in-Chief of Fundamental Toxicological Sciences, a sister journal of The Journal of Toxicological Sciences. Toshiyuki Kaji, Ph.D.Editor-in-ChiefThe Journal of Toxicological Sciences

著者

Masaya Motohashi Michael F. Wempe Tomoko Mutou Yuya Okayama Norio Kansaku Hiroyuki Takahashi Masahiro Ikegami Masao Asari Shin Wakui

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.195-206, 2016-04-01 (Released:2016-03-10)

参考文献数

36

被引用文献数

14 16

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This article was retracted. See the Notification.

著者

Tze-Kiong Er Eing-Mei Tsai Li-Yu Tsai Ying-Chin Ko Jau-Nan Lee

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.1, pp.75-82, 2006 (Released:2006-03-10)

参考文献数

46

被引用文献数

9 9

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Semen samples were obtained from 30 volunteers who had never consumed betel quid. Swim-up spermatozoa from the 30 seminal samples of non-betel quid chewers and also non-smokers, usually not exposed to passive smoking, were treated in vitro with arecoline at different concentrations to evaluate the action of these drugs on sperm motility. Highly motile sperms were collected and divided into 5 equal fractions. Four fractions were supplemented with various concentrations of arecoline and one as control. The study was carried out at time 0 and +1, +2, +3 and +4 hr of incubation. Sperm cells were also extracted and blotted with COX-2 antibody after arecoline treatment after 4 hr incubation. The sperm motility parameters, i.e., motility, average path velocity, curvilinear velocity, straight-line velocity and linearity, were significantly decreased after arecoline treatment. In vitro, arecoline induces the COX-2 expression of sperm cells in a dose-dependent manner. This is the first report to demonstrate that arecoline may mediate COX-2 expression in human sperms, resulting in inflammation response. This situation may act on the structure responsible for the flagellar motion and cause the reduction of sperm motility.

著者

Takako GOTOHDA Aki KUWADA Kyoji MORITA Shin-ichi KUBO Itsuo TOKUNAGA

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.25, no.3, pp.223-231, 2000-08-17 (Released:2008-02-21)

参考文献数

39

被引用文献数

11 12

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Toluene, a commonly used industrial solvent, is known to be toxic to both neuronal and glial cells, and has been shown to increase the immunoreactivity of glial fibrillary acidic protein(GFAP)in the brain. However, the mechanism of toluene-induced GFAP expression is poorly understood. Recently, GFAP mRNA expression in cultured astrocytes has been shown to be modulated by various steroid hormones, such as progesterone, testosterone, and their 5α-reduced metabolites. Therefore, it seems possible that steroid hormones may play a potential role in the enhancement of GFAP expression observed following toluene exposure. To address this possibility, the effect of toluene inhalation on the expression of mRNAs encoding GFAP and steroidogenic enzymes in rat brain was examined. Toluene exposure increased GFAP protein contents without any significant alteration in GFAP mRNA levels in the hippocampus. In contrast, the elevation of both GFAP protein contents and its mRNA levels was observed in the cerebellum following toluene exposure. Further studies indicated that toluene exposure increased steroid 5α-reductase(5α-R)mRNA levels prior to the elevation of GFAP mRNA in the cerebellum, whereas neither 5α-R nor GFAP mRNA levels in the hippocampus were significantly affected by toluene exposure. These results suggest that toluene inhalation may enhance GFAP gene expression in the rat cerebellum, and propose the possibility that the elevation of 5α-R expression, and hence 5α-reduced metabolites of steroid hormones, is presumably related to toluene-induced GFAP mRNA expression.

著者

山下 衛

出版者

一般社団法人 日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.23, no.SupplementV, pp.App145-App160, 1998-11-26 (Released:2008-02-21)

著者

Ayano Hasegawa Takahiro Sasaki Jahidul Islam Takashi Tominaga Tomonori Nochi Kenshiro Hara Kentaro Tanemura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.3, pp.149-159, 2023 (Released:2023-03-01)

参考文献数

32

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Reportedly, antibiotics, which are frequently prescribed in children, have long-term effects owing to gut microbiota dysregulation. Tosufloxacin tosilate hydrate (TFLX) is the first orally administered new quinolone with high efficacy and broad-spectrum action approved as an antibacterial agent for pediatric use in Japan. However, studies on the effects of its early-stage administration are limited. Therefore, we aimed to analyze the later effects of its developmental administration by monitoring growth rate, neurobehavior, and gut microbiota in mice. The TFLX was administered via drinking water at a dose of up to 300 mg/kg for two consecutive weeks during the developmental period (4–6 weeks of age) or adulthood (8–10 weeks of age). Thereafter, the body weights of the mice were measured weekly to monitor growth rate. Behavioral tests were also conducted on 11–12-week-old mice to examine the neurobehavioral effects of the treatment. Further, to examine the effects of the treatment on microbiota, fecal samples were collected from the rectum of mice dissected at 12 weeks of age, and 16s rRNA analysis was conducted. Our results showed increased body weights after TFLX administration, without any long-term effects. Behavioral analysis suggested alterations in anxiety-like behaviors and memory recall dysregulation, and gut microbiota analysis revealed significant differences in bacterial composition. These findings indicated that TFLX administration during the developmental period affects mice growth rate, neurobehavior, and gut microbiota structure. This is the first study to report that TFLX is potentially associated with the risk of long effects.

著者

Atsushi Watanabe Shigeki Yoneyama Mikio Nakajima Norihiro Sato Ryoko Takao-Kawabata Yukihiro Isogai Aki Sakurai-Tanikawa Kazuhiro Higuchi Akihito Shimoi Hideyuki Yamatoya Kenji Yoshida Terutomo Kohira

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.37, no.3, pp.617-629, 2012-06-01 (Released:2012-06-01)

参考文献数

14

被引用文献数

57 69

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Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 μg/kg/day. The non-carcinogenic dose level was 4.5 μg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.

著者

Tomoya Fujie Ayumi Muraoka Keisuke Ito Yusuke Ozaki Chika Yamamoto Toshiyuki Kaji

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.11, pp.493-501, 2022 (Released:2022-11-01)

参考文献数

35

被引用文献数

4

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Lead (Pb) is an environmental pollutant that adversely affects various organs in the human body and is a well-known risk factor for cardiovascular diseases, caused by the dysfunction of vascular endothelial cells that cover the luminal surface of the blood vessels. The Zrt- and Irt-like related protein (ZIP) transporter ZIP8 is one of the primary importers of zinc, iron, manganese, and cadmium, and its expression appears to be important for the metabolism of these metals. In the present study, we investigated the influence of ZIP8 on Pb-induced cytotoxicity in vascular endothelial cells, induction of ZIP8 expression by Pb, and its mechanism of action in vascular endothelial cells. The study revealed the following: (1) Pb cytotoxicity in vascular endothelial cells was potentiated by the knockdown of ZIP8, but the intracellular accumulation of Pb in the cells remain unaffected; (2) Pb induced the expression of ZIP8; (3) the induction of ZIP8 expression by Pb was mediated by nuclear factor (NF)-κB signaling pathway; and (4) Pb activated p38, mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK), but the activation of these MAPKs was not involved in the induction of ZIP8 by Pb. Therefore, the study shows that Pb induces the expression of endothelial ZIP8 and this induction appears to be involved in the protection against Pb cytotoxicity by intracellular Pb accumulation independent mechanisms.

著者

Miho Sakakibara Yosuke Maeda Kazuichi Nakamura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.8, pp.327-336, 2022 (Released:2022-08-01)

参考文献数

29

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We used an abortion-prone mouse model, generated by mating female CBA/J mice with male DBA/2JJcl mice, to examine the effects of changes in the Th1/Th2 cell ratio and the percentage of regulatory T (Treg) cells on the maintenance of pregnancy. We subcutaneously injected female CBA/J mice once each with 50 μg/mouse of Dermatophagoides farinae (Df) extract and the squalene-based adjuvant (SquA); 10 days later, these mice were mated with male DBA/2JJcl mice. Compared with injection of vehicle or adjuvant, the Df treatment decreased the Th1/Th2 cell ratio and concomitantly increased the percentage of Treg cells in the spleen. In addition, fetal death rates were decreased. We then explored a substance which shifted the Th1/Th2 balance toward Th1 side. We found that 50 μg/mouse of keyhole limpet hemocyanin (KLH) increased the splenic Th1/Th2 cell ratio of nonpregnant female CBA/J mice. We subcutaneously injected female CBA/J mice with KLH and SquA; 10 days later, these mice were mated with male DBA/2JJcl mice. Compared with injection of vehicle or adjuvant, treatment with KLH enhanced the Th1 bias during pregnancy and increased the fetal death rate. The percentage of Treg cells, however, was increased in these KLH-injected pregnant mice contrary to our presumption. All collected data showed strong positive correlation between the Th1/Th2 cell ratio and fetal death rate. The increase in Treg cells independent of effects on the fetal death rate suggests that Treg cells do not necessarily induce maternal tolerance to the fetus but may prevent excessive Th1/Th2 imbalance during pregnancy.

著者

ZheZhe Guan YaLan Li ShaoCong Hu CaiFeng Mo DongLing He Zhi Huang Ming Liao

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.10, pp.389-407, 2022 (Released:2022-09-14)

参考文献数

65

被引用文献数

1

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Trimeresurus stejnegeri is one of the top ten venomous snakes in China, and its bite causes acute and severe diseases. Elucidating the metabolic changes of the body caused by Trimeresurus stejnegeri bite will be beneficial to the diagnosis and treatment of snakebite. Thus, an animal pig model of Trimeresurus stejnegeri bite was established, and then the metabolites of serum and urine were subsequently screened and identified in both ESI+ and ESI- modes identified by ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) methods. There are 9 differential metabolites in serum, including Oleic acid, Lithocholic acid, Deoxycholic acid, Hypoxanthine, etc. There are 11 differential metabolites in urine, including Dopamine, Thiocysteine, Arginine, Indoleacetaldehyde, etc. Serum enrichment pathway analysis showed that 5 metabolic pathways, including Tryptophanuria, Liver disease due to cystic fibrosis, Hartnup disease, Hyperbaric oxygen exposure and Biliary cirrhosis, the core metabolites in these pathways, including deoxycholic acid, lithocholic acid, tryptophan and hypoxanthine, changed significantly. Urine enrichment pathway analysis showed that 4 metabolic pathways, including Aromatic L-Amino Acid Decarboxylase, Vitiligo, Blue Diaper Syndrome and Hyperargininemia, the core metabolites in these pathways including dopamine, 5-hydroxyindole acetic acid and arginine. Taken together, the current study has successfully established an animal model of Trimeresurus stejnegeri bite, and identified the metabolic markers and metabolic pathways of Trimeresurus stejnegeri bite. These metabolites and pathways may have potential application value and provide a therapeutic basis for the treatment of Trimeresurus stejnegeri bite.

著者

Satoshi Tamai Takuma Iguchi Noriyo Niino Kei Mikamoto Ken Sakurai Ayako Sayama Hitomi Shimoda Wataru Takasaki 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.42, no.1, pp.73-84, 2017-02-01 (Released:2017-01-07)

参考文献数

44

被引用文献数

6 8

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Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

著者

Ryo Ichikawa Sosuke Masuda Junta Nakahara Mio Kobayashi Risako Yamashita Suzuka Uomoto Ohshima Kanami Erika Hara Yuko Ito Makoto Shibutani Toshinori Yoshida

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.7, pp.289-300, 2022 (Released:2022-07-01)

参考文献数

43

被引用文献数

1

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To study the effects of autophagy inducer carbamazepine (CBZ) in a high-fat diet (HFD)/streptozotocin (STZ)-related early hepatocarcinogenesis model, we determined autophagic flux by immunohistochemical analysis of autophagy marker expression in preneoplastic liver foci and compared that with the expression of the NADPH oxidase subunit. Male F344 rats were fed a basal diet or HFD and subjected to two-stage hepatocarcinogenesis; diabetes mellitus was induced via STZ administration. Several STZ-treated, HFD-fed rats were administered CBZ (a total of five doses every one or two days) at week 7 and 8. STZ-treated, HFD-fed rats decreased β cells in the islet of Langerhans and increased adipophilin-positive lipid droplets in the liver; moreover, they had a larger area of glutathione S-transferase placental form-immunopositive preneoplastic liver foci, which was associated with inhibition of autophagy and induction of the NADPH oxidase subunit, as demonstrated by increased immunohistochemical expression of an autophagosome receptor marker microtubule-associated protein light chain 3 (LC3)-binding protein p62, and of an NADPH oxidase subunit p22phox in the preneoplastic foci. An increased trend of an autophagy phagophore marker LC3 in preneoplastic foci was also detected. CBZ administration could induce autophagy and impair p22phox expression, as shown by altered expression of autophagy regulators (Atg5, Atg6, Lamp1, Lamp2, and Lc3), NADPH oxidase subunits (P22phox and P67phox), and antioxidant enzymes Gpx1 and Gpx2. These results suggest that inhibition of autophagy and induction of p22phox might contribute to HFD/STZ-related early hepatocarcinogenesis in rats; however, the effects of CBZ administration on the STZ/HFD-increased preneoplastic foci were marginal in this study.

著者

Yukiko Yamazaki-Hashimoto Yuji Nakamura Hiroshi Ohara Xin Cao Ken Kitahara Hiroko Izumi-Nakaseko Kentaro Ando Hiroshi Yamazaki Takanori Ikeda Junichi Yamazaki Atsushi Sugiyama

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.40, no.1, pp.33-42, 2015-02-01 (Released:2014-12-18)

参考文献数

39

被引用文献数

9 11

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Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

著者

Koya Sato Seigo Sanoh Yuji Ishida Chise Tateno Shigeru Ohta Yaichiro Kotake

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.7, pp.277-288, 2022 (Released:2022-07-01)

参考文献数

40

被引用文献数

3

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Felbamate (FBM) is an antiepileptic drug that has minimal toxicity in preclinical toxicological species but has a serious idiosyncratic drug toxicity (IDT) in humans. The formation of reactive metabolites is common among most drugs associated with IDT, and 2-phenylpropenal (2-PP) is believed to be the cause of IDT by FBM. It is important to consider the species difference in susceptibility to IDT between experimental animals and humans. In the present study, we used an in vitro and in vivo model system to reveal species difference in IDT of FBM. Human cytochrome P450 (CYP) and carboxylesterase (CES) expressing microsomes were used to clarify the isozymes involved in the metabolism of FBM. The remaining amount of FBM was significantly reduced in incubation with microsomes expressing human CYP2C8, 2C9, 2E1, and CES1c isozymes. Chimeric mice with humanized liver are expected to predict IDT in humans. Therefore, metabolite profiles in chimeric mice with humanized liver were investigated after administration of FBM. Metabolites after glutathione (GSH) conjugation of 2-phenylpropenal (2-PP), which is the reactive metabolite responsible for FBM-induced IDT, were detected in chimeric mice plasma and liver homogenate. Mass spectrometry imaging (MSI) visualizes distribution of FBM and endogenous GSH, and GSH levels in human hepatocyte were decreased after administration of FBM. In this study, we identified CYP and CES isozymes involved in the metabolism of FBM and confirmed reactive metabolite formation and subsequent decrease in GSH using humanized animal model. These results would provide useful information for the susceptibility to IDT between experimental animals and humans.