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Journal of Toxicological Sciences

Kazuto Narita, Yuuki Ishii, Phuc Thi Hong Vo, Fumiko Nakagawa, Shinichi Ogata, Kunihiko Yamashita, Hajime Kojima, Hiroshi Itagaki
Recently, animal testing has been affected by increasing ethical, social, and political concerns regarding animal welfare. Several in vitro safety tests for evaluating skin sensitization, such as the human cell line activation test (h-CLAT), have been proposed. However, similar to other tests, the h-CLAT has produced false-negative results, including in tests for acid anhydride and water-insoluble chemicals. In a previous study, we demonstrated that the cause of false-negative results from phthalic anhydride was hydrolysis by an aqueous vehicle, with IL-8 release from THP-1 cells, and that short-time exposure to liquid paraffin (LP) dispersion medium could reduce false-negative results from acid anhydrides...
2018: Journal of Toxicological Sciences
Satoshi Kitaoka, Jo Hatogai, Wataru Ochiai, Kiyoshi Sugiyama
The drug-metabolizing enzyme CYP3A is a heterogeneous enzyme found in the liver that displays local characteristics referred to as "zonation." Zonation contributes to improved energy efficiency in metabolism. The objective of this study was to determine a scientific basis for the safety of fetuses and nursing infants in cases in which the use of pharmaceuticals by pregnant and nursing mothers is unavoidable. In addition, we analyzed CYP3A zonation in the liver using mice from the fetus stage to the nursing stage...
2018: Journal of Toxicological Sciences
Shintaro Sugahara, Kumiko Fukuhara, Yuki Tokunaga, Shuhei Tsutsumi, Yuto Ueda, Masateru Ono, Katsuhisa Kurogi, Yoichi Sakakibara, Masahito Suiko, Ming-Cheh Liu, Shin Yasuda
1-Naphthol (1-Nap) and 2-naphthol (2-Nap) are phenolic isomers that may be subjected to sulfate conjugation in vivo. Phase-II sulfate conjugation of phenolic compounds is generally thought to result in their inactivation. This study aimed to investigate the antioxidative effects of 1-NapS and 2-NapS, in comparison with their unsulfated counterparts, using established free radical scavenging assays. Based on the calculated EC50 values, 1-NapS resulted in 5.60 to 7.35-times lower antioxidative activity than 1-Nap...
2018: Journal of Toxicological Sciences
Yu Haranosono, Hiroki Ueoka, Gakushi Kito, Shingo Nemoto, Masaaki Kurata, Hideyuki Sakaki
Most of the α-halo carbonyl (AHC) compounds tend to be predicted as mutagenic by structure-activity relationship based on structural category only, because they have an alkyl halide structure as a structural alert of mutagenicity. However, some AHC compounds are not mutagenic. We hypothesized that AHC reacts with DNA by SN 2 reaction, and the reactivity relates to mutagenicity. As an index of SN 2 reactivity, we focused on molecular orbitals (MOs), as the direction and position of two molecules in collision are important in the SN 2 reaction...
2018: Journal of Toxicological Sciences
Naho Hirayama, Toshihiko Aki, Takeshi Funakoshi, Kanako Noritake, Kana Unuma, Koichi Uemura
Paraquat (PQ) is an herbicide that was once used worldwide, but is now prohibited in many nations due to its high toxicity to humans. However, there are still rare cases of the fetal intoxication of PQ, which was purchased prior to the prohibition in Japan. In this study, several cell death pathways, the mitochondrial stress response, and autophagy were examined in SH-SY5Y cells exposed to PQ. The results reveal the decrease of a mitochondrial stress sensitive-BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) protein, the suppression of autophagic flux, and the lack of apoptosis as well as other regulated forms of necrosis, such as necroptosis and ferroptosis...
2018: Journal of Toxicological Sciences
Kentaro Ando, Yuji Nakamura, Mihoko Hagiwara-Nagasawa, Hiroyuki Harada, Hiroyoshi Miyamoto, Naoki Inamura, Kan Takagi, Ai Goto, Koki Chiba, Nur Jaharat Lubna, Hiroko Izumi-Nakaseko, Atsuhiko T Naito, Atsushi Sugiyama
In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition...
2018: Journal of Toxicological Sciences
Fan Wu, Jinying Zhang
Epidemiological studies have confirmed that ambient fine particulate matter (PM2.5 ) exposure is associated with cardiovascular disease (CVD). However, the underlying mechanisms in PM2.5 exposure-induced heart injury are largely unknown. It has been acknowledged that NADPH oxidase (Nox) 4 plays a critical role in CVD development. To investigate the acute effects of PM2.5 on the mouse heart and the role of Nox4 in PM2.5 exposure-induced cardiac injury, C57BL/6J mice were instilled with saline or 1.5, 3.0, 6...
2018: Journal of Toxicological Sciences
Sailendra Nath Sarma, Ammar Saleem, Jin-Yong Lee, Maki Tokumoto, Gi-Wook Hwang, Hing Man Chan, Masahiko Satoh
Cadmium (Cd) is a common environmental pollutant with known toxic effects on the kidney. Urinary metabolomics is a promising approach to study mechanism by which Cd-induced nephrotoxicity. The aim of this study was to elucidate the mechanism of Cd toxicity and to develop specific biomarkers by identifying urinary metabolic changes after a long-term of Cd exposure and with the critical concentration of Cd in the kidney. Urine samples were collected from wild-type 129/Sv mice after 67 weeks of 300 ppm Cd exposure and analyzed by ultra performance liquid chromatography connected with quadrupole time of flight mass spectrometer (UPLC-QTOF-MS) based metabolomics approach...
2018: Journal of Toxicological Sciences
Eita Sasaki, Tsuyoshi Yokoi
Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs...
2018: Journal of Toxicological Sciences
Pattama Singhirunnusorn, Benchamart Moolmuang, Kriengsak Lirdprapamongkol, Mathuros Ruchirawat
Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine released by immune cells during inflammation process. Sodium arsenite (NaAsO2 ) is an environmental toxic metal. The effects of excess NaAsO2 on TNF-α response and its intracellular signaling are not well understood. We hypothesized that NaAsO2 exposure might affect cellular response to TNF-α. Using HeLa cell model, we found that the combination of NaAsO2 and TNF-α clearly decreased cell viability and mitochondrial membrane potential, but increased percentage of early and late apoptotic cells and cleaved-poly (ADP-ribose) polymerase (PARP)...
2018: Journal of Toxicological Sciences
Hideaki Yokoyama, Akio Kobayashi, Kazuma Kondo, Shin-Ichi Oshida, Tadakazu Takahashi, Taku Masuyama, Toshiyuki Shoda, Shoichiro Sugai
Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT-553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re-synthesis of TG) in the enterocytes of the small intestine leading to suppression of a postprandial elevation of plasma lipids. After repeated oral dosing JTT-553 in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity...
2018: Journal of Toxicological Sciences
Hiroki Yoshioka, Tsunemasa Nonogaki, Yasuro Shinohara, Masumi Suzui, Yurie Mori, Gi-Wook Hwang, Katsumi Ohtani, Nobuhiko Miura
The aim of the present study is to investigate the "chronotoxicity" of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, or Fe) by assessing how their toxicity varies with circadian periodicity. Male ICR mice were injected with each metal compound intraperitoneally at 6 different time points over the course of a day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22). Mortality was then monitored until 14 days after the injection. Our investigation demonstrated that mice were tolerant against Ni toxicity during dark phase, on the other hand, they were tolerant against Cr toxicity during light phase...
2018: Journal of Toxicological Sciences
Michiharu Matsumoto, Hirokazu Kano, Masaaki Suzuki, Tadashi Noguchi, Yumi Umeda, Shoji Fukushima
The carcinogenicity of quinoline was examined by administrating quinoline in the drinking water to groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of each sex. In rats, the doses of quinoline were 0, 200, 400, and 800 ppm for males and 0, 150, 300, and 600 ppm for females. In male rats, administration of quinoline was terminated at week 96 due to high mortality caused by tumors. There were significant increases of hepatocellular adenomas, hepatocellular carcinomas, hepatocellular adenomas and/or carcinomas (combined), and liver hemangiomas, hemangiosarcomas, hemangiomas and/or hemangiosarcomas (combined) in both male and female rats, and nasal esthesioneuroepitheliomas and sarcoma NOS (not otherwise specified) in males...
2018: Journal of Toxicological Sciences
Xiaoting Jin, Bin Xue, Qunfang Zhou, Ruijun Su, Zhuoyu Li
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...
2018: Journal of Toxicological Sciences
Satoshi Kitaoka, Jo Hatogai, Ryuki Iimura, Yuka Yamamoto, Konomi Oba, Mami Nakai, Yoshiki Kusunoki, Wataru Ochiai, Kiyoshi Sugiyama
The use of midazolam in early stages of pregnancy has resulted in a high incidence of birth defects; however, the underlying reason is unknown. We investigated expression changes of the CYP3A molecular species and focused on its midazolam metabolizing activity from the foetal period to adulthood. CYP3A16 was the only CYP3A species found to be expressed in the liver during the foetal period. However, CYP3A11 is upregulated in adult mice, but has been found to be downregulated during the foetal period and to gradually increase after birth...
2018: Journal of Toxicological Sciences
Masahiro Iwaki, Toshiro Niwa, Yukiko Nakamura, Atsushi Kawase, Hiroshi Komura
The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R- and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53...
2018: Journal of Toxicological Sciences
Kaoru Toyoda, Yusuke Suzuki, Kyotaka Muta, Taku Masuyama, Kochi Kakimoto, Akio Kobayashi, Toshiyuki Shoda, Shoichiro Sugai
Diabetic nephropathy (DN) is one of the complications of diabetes and is now the most common cause of end-stage renal disease. Fructose is a simple carbohydrate that is present in fruits and honey and is used as a sweetener because of its sweet taste. Fructose has been reported to have the potential to progress diabetes and DN in humans even though fructose itself does not increase postprandial plasma glucose levels. In this study, we investigated the effects of high fructose intake on the kidney of the Spontaneously Diabetic Torii (SDT) rats which have renal lesions similar to those in DN patients and compared these with the effects in normal SD rats...
2018: Journal of Toxicological Sciences
Limeng Wang, Zhihua Yang, Long Xu, Xiujie Pan, Xingyu Liu, Junwei Zhao, Xiang Li, Maoxiang Zhu, Jianping Xie
Crotonaldehyde is a ubiquitous air pollutant in the environment. It is reported to be harmful to the biosystems in vivo and in vitro. The exposure to crotonaldehyde irritates the mucous membranes and induces edema, hyperemia, cell necrosis, inflammation, and acute respiratory distress syndrome in the lungs. However, the effects of crotonaldehyde on the immune system have not been reported. In the present study, 6-8 weeks old male Wistar rats were exposed to crotonaldehyde by intratracheal instillation at doses of 4, 8, and 16 μL/kg body weight (b...
2018: Journal of Toxicological Sciences
Yasuhiro Ishihara, Nami Ikeda-Ishihara, Chihaya Koriyama, Noriaki Kakiuchi, Masayuki Tanaka, Christoph F A Vogel, Toshihiro Kawamoto, Mayumi Tsuji
Many different types of chemicals are used in industry, and occupational allergies are becoming a serious problem in the field of industrial hygiene. In this study, we employed a novel enzyme-linked immunosorbent assay (ELISA) with partial peptides of human serum albumin (HSA) to quantify chemical-specific immunoglobulin G (IgG) in serum for evaluating exposure to chemicals. When HSA partial peptides containing lysine residues were mixed with formaldehyde (FA) or phthalic anhydride (PA), almost all lysine residues were lost...
2018: Journal of Toxicological Sciences
Hisaka Kurita, Tatsuya Hasegawa, Yoshiyuki Seko, Hisamitsu Nagase, Maki Tokumoto, Jin-Yong Lee, Masahiko Satoh
Cadmium (Cd) is an environmental pollutant present in contaminated water, food and soil. Cd adversely affects fetal development. We exposed pregnant mice to daily oral doses of 5 and 10 mg/kg Cd and examined fetal growth. It was demonstrated that the exposure to Cd (10 mg/kg) during gestation caused fetal growth retardation (FGR). Investigation of the ubiquitin-proteasome system in fetal livers of mice exposed to gestational Cd revealed increased polyubiquitinated protein accumulation, contrasting with decreased levels of monoubiquitin protein...
2018: Journal of Toxicological Sciences
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