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Journal of Toxicological Sciences

Shuji Ogawa, Hiroyuki Kuroda, Toshiko Kinomoto, Yoshihiro Kawabata, Mayumi Kawabe, Mayuko Suguro, Yuji Oishi
There is sometimes controversy over whether or not statistically significant responses produced in carcinogenicity studies have biologically significance. Ambiguous results from our previous two-year oral carcinogenicity study on acotiamide hydrochloride hydrate (acotiamide-HH), a prokinetic drug for functional dyspepsia, in rats made it unclear whether the drug may exhibit uterine carcinogenicity. To check this finding, we performed a second long-term carcinogenicity study using two identical control groups to more accurately evaluate uterine carcinogenesis by considering the incidence of spontaneous neoplasms...
2018: Journal of Toxicological Sciences
Yongmin Xu, Dazhuang Sun, Chunqing Song, Rui Wang, Xuesong Dong
OBJECTIVE: To investigate the protective effect and underlying mechanism of the superoxide dismutase mimic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), on paraquat (PQ)-induced lung alveolar epithelial-like cell injury. METHODS: Lung alveolar epithelial-like cells (A549) were pretreated with 10 μM MnTMPyP for 1.5 hr and then cultured with or without PQ (750 uM) for 24 hr. Cell survival was determined using the MTT assay. Apoptosis, mitochondrial transmembrane potential, reactive oxygen species (ROS) production, and Ca2+ levels were measured using flow cytometry...
2018: Journal of Toxicological Sciences
Masayo Hirao-Suzuki, Shuso Takeda, Takanobu Kobayashi, Katsuhito Kino, Hiroshi Miyazawa, Michael P Waalkes, Masufumi Takiguchi
There is adequate evidence for the carcinogenicity of cadmium (Cd). However, a significant unaddressed question remains as to how this metal actually causes malignant transformation (tumor initiation). Since it has been shown that Cd only has the weak direct interaction potential with DNA, the metal is recognized as an indirect genotoxicant and mutagen. Currently, Cd-mediated "epigenetic" modifications, such as changes in DNA methylation resulting in alteration in target gene expression, coupled with cancer progression, are the focus of mechanistic research...
2018: Journal of Toxicological Sciences
Tetsuya Fujimoto, Shuji Aou
Perinatal exposure to bisphenol A (BPA) causes several alterations in brain function and behavior. In previous studies, we showed that prenatal treatment with low-level BPA impaired gender-specific behavior, enhanced depression-like behavior, and augmented behavioral responses to predator odor in rats. On this premise, we hypothesized that BPA-treated rats were more susceptible to predator odor stress. To test the potential neural mechanism underlying this effect, we conducted an electrophysiological study of neurons in the medial amygdala-a regional component of the olfactory pathway with high estrogen and androgen receptor expression, and thus a potential target of BPA-in rats exposed to BPA...
2018: Journal of Toxicological Sciences
Ryuji Watari, Motoharu Kakiki, Ayumi Oshikata, Toshiaki Takezawa, Chihiro Yamasaki, Yuji Ishida, Chise Tateno, Yukie Kuroda, Seiichi Ishida, Kazutomi Kusano
During drug discovery, in vitro models are used to predict the in vivo pharmacokinetic and toxicological properties of drug candidates in humans. However, the conventional method of culturing human hepatocytes as monolayers does not necessarily replicate biologic reactions and does not support liver-specific functions, such as cytochrome P450 (CYP) activities, for prolonged periods. To remedy these problems and thus increase and prolong hepatic functions, we developed a culture system comprising a collagen vitrigel membrane (CVM) chamber and PXB-cells®, fresh hepatocytes isolated from liver-humanized chimeric mice (PXB-mice®)...
2018: Journal of Toxicological Sciences
Kunihiko Yamashita, Hiroshi Miyazaki, Shinsuke Shinoda, Saori Hagiwara, Hirohito Takahashi, Hiroshi Itagaki
We evaluated the skin sensitizing potential of 10 natural organic chemicals, or their derivatives, which are included in foods and/or skin products, using a modified local lymph node assay (LLNA), with an elicitation phase (LLNA:DAE). The following compounds were tested: carminic acid, esculetin, 4-methyl esculetin, coumarin, quercetin, curcumin, naringenin, chlorogenic acid, isoscopoletin, and shikonin. Esculetin, 4-methyl esculetin, isoscopoletin, and shikonin yielded positive results. In particular, shikonin at a very low concentration (0...
2018: Journal of Toxicological Sciences
Nur Jaharat Lubna, Yuji Nakamura, Mihoko Hagiwara-Nagasawa, Ai Goto, Koki Chiba, Kumiko Kitta, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T Naito, Yasuki Akie, Atsushi Sugiyama
We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na+ , Ca2+ and K+ channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion...
2018: Journal of Toxicological Sciences
Takehito Isobe, Masaki Honda, Ryuichi Komatsu, Mitsuyasu Tabo
We used motion field imaging to characterize the conduction and contraction of a sheet of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs). A hiPS-CMs sheet of 2.8 mm × 2.8 mm allowed us to simultaneously measure the conduction and the contraction properties in the same cells. Pharmacological responses in the hiPS-CMs of four typical cardiac functional modulators, Na+ channel blocker (lidocaine), Ca2+ channel blocker (diltiazem), gap-junction inhibitor (carbenoxolone), and β-adrenergic stimulator (isoproterenol), were investigated, and the results were compared to those found using the isolated guinea-pig heart model perfused by the Langendorff method...
2018: Journal of Toxicological Sciences
Min-Seok Kim, Jin-Young Han, Sung-Hwan Kim, Hyung-Young Kim, Doin Jeon, Kyuhong Lee
Polyhexamethylene guanidine phosphate (PHMG) is an antimicrobial biocide that causes severe lung injury accompanied with inflammation and subsequent fibrosis. Cytokines mediate the inflammatory response, leading to fibrosis in injured tissues. PHMG is known to induce the expression of various cytokines in vitro and in vivo. In the present study, we investigated the involvement of three MAPK subfamilies (JNK, p38 MAPK, and ERK) in PHMG-induced cytokine expression in A549 human lung epithelial cells. Our in vivo and in vitro data indicated that PHMG induced an increase in mRNA expression of IL-6 and TNF-α, and enhanced the phosphorylation of JNK, p38 MAPK, and ERK...
2018: Journal of Toxicological Sciences
Shigeo Suzuki, Yumie Morimoto-Kobayashi, Chika Takahashi, Yoshimasa Taniguchi, Mikio Katayama
It has been demonstrated that successive ingestion of matured hop extract (MHE), produced by extraction from heat-treated hops, results in body fat reduction in animals and humans; however, preclinical safety studies have not been reported. In this study, we conducted in vitro and in vivo safety studies for MHE. Genotoxicity was evaluated using the Ames test, in vitro chromosomal aberration test, and in vivo micronucleus test. To assess acute safety, a single, oral administration of MHE to rats was monitored...
2018: Journal of Toxicological Sciences
Changhua He, Koji Arizono, Hezhe Ji, Yuka Yakushiji, Daizhou Zhang, Kuangwei Huang, Yasuhiro Ishibashi
Total mercury (THg) and methylmercury (MeHg) bioaccumulation was explored in the Bimastus parvus species of earthworm (B. parvus) native to the leachate-contaminated forest soils around a Hg-polluted traditional landfill in Japan. General soil properties and concentrations of THg and MeHg in forest soils and in B. parvus were determined. The results indicated that the average THg concentrations in B. parvus and in forest soils in the leachate-contaminated sites were 10.21 and 14.90 times higher than those in the reference sites, respectively, whereas similar average MeHg concentrations were observed in forest soils (< 0...
2018: Journal of Toxicological Sciences
Atsushi Fujiwara, Miki Shimosawa, Masahiko Iino, Mikio Sasaki, Shin-Ichi Sato, Akihito Shimoi
The purpose of this study was to investigate the discriminative stimulus properties of morphine and codeine using different administration routes to that used at drug discrimination training. Rats were trained to discriminate morphine at 3 mg/kg from saline by the intraperitoneal route in a standard two-lever drug discrimination paradigm. Generalization of morphine by the subcutaneous and the oral routes, and codeine by the intraperitoneal and the oral routes to the discriminative stimulus properties of the morphine training dose were investigated...
2018: Journal of Toxicological Sciences
Shohei Yoshimaru, Ryota Shizu, Satoshi Tsuruta, Yuto Amaike, Makoto Kano, Takuomi Hosaka, Takamitsu Sasaki, Kouichi Yoshinari
The nuclear receptor pregnane X receptor (PXR) plays a major role in the xenobiotic-induced expression of drug-metabolizing enzymes. PXR activation is also associated with several adverse events in the liver. Especially, the receptor enhances hepatocyte proliferation mediated by chemical liver tumor promoters, suggesting that exposure to PXR activators increases the risk of liver cancer. In this study, we have investigated the influences of food additives on PXR to understand their potential adverse effects when they are taken in combination with other chemical compounds...
2018: Journal of Toxicological Sciences
Atsushi Watanabe, Kazuyuki Tsurui, Shigeki Yoneyama, Hijiri Iwata, Takayuki Anzai, Christopher Jerome, Dai Nakae
Teriparatide, a drug used in the treatment of osteoporosis, was administered to rats subcutaneously for the duration of 3 months, at a frequency of either once weekly or once daily to demonstrate the varying levels of anabolic action the drug can have on bone depending on the dosing frequency. The levels of biomarkers in the blood were compared and found to vary in osteocalcin (OC), a biomarker of bone formation, and cross-linked N-telopeptide of type 1 collagen (NTx), a biomarker of bone resorption, according to the dosing frequency...
2018: Journal of Toxicological Sciences
Takeshi Toyoda, Young-Man Cho, Jun-Ichi Akagi, Yasuko Mizuta, Kohei Matsushita, Akiyoshi Nishikawa, Katsumi Imaida, Kumiko Ogawa
Although obesity is increasing worldwide, experimental studies examining the possible association between obesity and susceptibility to chemical toxicity are limited. In the present study, we performed a 13-week toxicity study for acetaminophen (APAP), a well-known drug that exhibits hepatotoxicity as an adverse effect, using an obese rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 80, 253, 800, 2,530, or 8,000 ppm APAP in the diet for 13 weeks...
2018: Journal of Toxicological Sciences
Takayuki Abo, Takuo Yuki, Rui Xu, Daisuke Araki, Yutaka Takahashi, Hitoshi Sakaguchi, Hiroshi Itagaki
The Short Time Exposure (STE) test method is an in vitro method for assessing the eye irritation potential of chemicals and is used to classify the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Category 1 and No Category (NC). The method has been adopted by the Organisation for Economic Co-operation and Development (OECD) as test guideline (TG) 491 since 2015. While this method can be used to classify GHS NC, it is not suitable for testing highly volatile substances and solids other than surfactants...
2018: Journal of Toxicological Sciences
Keisuke Goda, Kosuke Saito, Kyotaka Muta, Akio Kobayashi, Yoshiro Saito, Shoichiro Sugai
Valproic acid (VPA) is known to induce hepatic steatosis due to mitochondrial toxicity in rodents and humans. In the present study, we administered VPA to SD rats for 3 or 14 days at 250 and 500 mg/kg and then performed lipidomics analysis to reveal VPA-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. VPA induced hepatic steatosis at the high dose level without any degenerative changes in the liver on day 4 (after 3 days dosing) and at the low dose level on day 15 (after 14 days dosing)...
2018: Journal of Toxicological Sciences
Makiko Shimizu, Hiroshi Suemizu, Sawa Mizuno, Takashi Kusama, Tomonori Miura, Shotaro Uehara, Hiroshi Yamazaki
Medicinal carnitine-derived and dietary-derived malodorous trimethylamine and its non-malodorous metabolite trimethylamine N-oxide were historically regarded as nontoxic. Clinical and toxicological interest has recently arisen because of their potential association with atherosclerosis. We previously reported a human physiologically based pharmacokinetic (PBPK) model for trimethylamine and its primary metabolite, trimethylamine N-oxide, based on reported rat trimethylamine pharmacokinetics. However, rats are poor metabolizers with respect to trimethylamine N-oxygenation, and this species difference was investigated in vitro using substrate depletion rates in rat and human liver microsomes...
2018: Journal of Toxicological Sciences
Weiwei Huang, Juan Chang, Ping Wang, Chaoqi Liu, Qingqiang Yin, Qun Zhu, Fushan Lu, Tianzeng Gao
Aflatoxin B1 (AFB1 ) and zearalenone (ZEA) are the secondary toxic metabolites of fungi which contaminate a wide range of food and feedstuffs. Limiting exposure of humans and livestock to them is very essential. Among numerous methods of mycotoxin-degradation, biodegradation by microorganisms and enzymes is an effective and promising approach to eliminate their hazards. The present study aims to optimize the proportion of different species of beneficial microbes by means of response surface methodology (RSM) and its combination with mycotoxin-degradation enzymes...
2018: Journal of Toxicological Sciences
Norie Murayama, Hiroshi Suemizu, Shotaro Uehara, Takashi Kusama, Marina Mitsui, Yusuke Kamiya, Makiko Shimizu, F Peter Guengerich, Hiroshi Yamazaki
Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity-attributable to drug metabolism and disposition, but having immunomodulatory properties-is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0...
2018: Journal of Toxicological Sciences
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