Fundamental Toxicological Sciences

2017 - Vol. 4 No. 6

2017 - Vol. 4

Original Article
General toxicity of a vitamin K1 2,3-epoxide reductase (VKOR) inhibitor, 3-acetyl-5-methyltetronic acid, in rats Vol.4, No.6, p.285-293
Masashi Uchida , Yuka Sakaguchi , Yohei Miyamoto
Released: December 26, 2017
Abstract Full Text PDF[597K]

We previously reported that 3-acetyl-5-methyltetronic acid (AMT) had inhibitory effects on rat renal vitamin K1 2,3-epoxide reductase (VKOR), as well as anti-fibrotic effects on Thy-1 glomerulonephritis and cisplatin-induced renal fibrosis in rats. In the present study, we investigated the general toxicity of AMT in male Crl:CD (SD) rats following a single or 2-week oral administration. After a single oral dose up to 1,500 mg/kg, no death or bleeding tendency was observed in any animal. In the 2-week repeated toxicity study, we performed clinical observations, body weight measurements, a urinalysis, hematology, blood chemistry, gross autopsy, organ weight measurements, and histopathology. The result obtained showed significant decreases in the red blood cell count, hematocrit value, hemoglobin concentration, and urinary calcium. However, no bleeding tendency was observed, even at the highest dose of 400 mg/kg. We also confirmed that the oral bioavailability of AMT was 56.7% in a pharmacokinetic study, and the area under the blood concentration (AUC) at 400 mg/kg of the 2-week oral toxicity study in rats was markedly larger than that in renal fibrosis model rats at 30 mg/kg intravenously. We concluded that AMT does not cause systemic bleeding in rats at the dose levels which AMT showed anti-fibrotic effects.

Original Article
Hepatic glucose-dependent insulinotropic polypeptide expression is modified by supplementing high-dose thiamine in obese diabetic rats Vol.4, No.6, p.279-284
Yuka Kohda , Akie Maekita , Takao Tanaka , Hitoshi Matsumura
Released: December 21, 2017
Abstract Full Text PDF[1M]

Glucose toxicity and lipotoxicity are important states in obesity and diabetes. We previously reported that thiamine supplementation decreases body weight and visceral fat mass in rats with obesity-related diabetes. Glucose-dependent insulinotropic polypeptide (GIP) acts on pancreatic β cells to promote insulin secretion. According to established theory, GIP is derived from the gastrointestinal tract. We previously discovered increased expression of the GIP gene in the livers of obese rats with diabetes receiving high-dose thiamine. We referred to our previous dataset of gene expression analysis using a microarray for livers, which led to the new idea for the present study. We focused on “liver-derived GIP” to demonstrate GIP protein expression in the liver and visually present localization of GIP in the liver. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into two groups: an unsupplemented control group and a thiamine-supplemented group receiving 2 g of thiamine/L in drinking water for 51 weeks. GIP protein expression in the livers of OLETF rats at 55 weeks of age were determined by western blotting and immunohistochemical analysis. GIP protein expression in the liver was increased in thiamine-supplemented rats compared with that in controls, suggesting that it is involved in preventing and controlling obesity-related diabetic complications. The novel findings of this study that GIP is expressed in the liver, is likely to be added to the story regarding GIP modification of the obese diabetic state.

Effect of chronic cadmium exposure on the gene expression of Birc family in the mouse kidney and liver Vol.4, No.6, p.275-278
Jin-Yong Lee , Maki Tokumoto , Gi-Wook Hwang , Masahiko Satoh
Released: December 21, 2017
Abstract Full Text PDF[1M]

Cadmium (Cd) is a toxic metal that can cause renal proximal tubular cell damage. Our previous research demonstrated that Cd induces apoptosis by suppressing the BIRC3 gene expression in human proximal tubular cells (HK-2 cells). BIRC3, a member of BIRC family, inhibits apoptosis by suppressing caspase activity. Cd has been shown to induce caspase-3 activation through the suppression of BIRC3 expression in HK-2 cells. In this study, we examined Birc family gene expression in the kidney and liver of mice exposed to Cd for 67 weeks. Cd exposure decreased the expression of Birc3 in the kidney but increased Birc3 expression in the liver of mice. In our previous in vitro study, Cd decreased BIRC3 expression predominantly in proximal tubular cells. The present findings strongly indicate that the decrease in BIRC3 gene expression is implicated in the induction of apoptosis by Cd in proximal tubules.

Original Article
Effect of metallothionein on ethanol-induced hepatotoxicity in mice Vol.4, No.6, p.269-273
Maki Tokumoto , Kiyoshi Shibuya , Jin-Yong Lee , Chiharu Tohyama , Masahiko Satoh
Released: December 15, 2017
Abstract Full Text PDF[1M]

Metallothionein (MT) is a small, metal-binding protein that can act as a scavenger of free radicals. To determine whether MT is involved in ethanol-induced hepatotoxicity, which is known to occur through oxidative stress, we studied sensitivity to hepatotoxicity caused by ethanol in MT-null mice genetically deleted for MT-I and MT-II. MT-null mice and wild-type mice were i.p. administrated with ethanol (99.5%, 2.0 g/kg). The increase in GPT, GOT, and LDH activities in the serum of MT-null mice was significantly higher than in the wild-type mice 24 hr after ethanol treatment. Histopathological examination in the liver of ethanol-treated MT-null mice demonstrated vacuolar degeneration. In contrast, histopathologic change was less prominent in the liver of ethanol-treated wild-type mice. Moreover, ethanol increased lipid peroxidation levels only in the liver of MT-null mice. These results indicate that deletion of MT is associated with ethanol-induced severe hepatotoxicity through oxidative stress.

Original Article
Suppressive effect of Sasa veitchii extract on obesity induced by a high-fat diet through modulation of adipose differentiation in mice Vol.4, No.6, p.261-268
Hiroki Yoshioka , Mihoko Mori , Masae Yoshikawa , Hirohisa Fujii , Akito Nagatsu , Tsunemasa Nonogaki
Released: December 13, 2017
Abstract Full Text PDF[1M]

Obesity is a major health problem worldwide that is associated with the increased risk of type 2 diabetes and other chronic diseases. Sasa veitchii, which belongs to the Gramineae family, has various properties including anti-obesity properties. However, detailed mechanism of anti-obesity was not reported. This study aimed to investigate the therapeutic effect of Sasa veitchii leaf extract (SE) on obesity characteristics induced by a high-fat diet (HFD) such as hyperglycemia, insulin resistance, and inflammatory response. Four-week-old male ddY mice were freely fed a HFD or a normal diet (control) for 12 weeks. During the experimental 12-week period, treatment with saline or SE, 0.2 mL twice per day by oral gavage, was conducted, and body weight was measured weekly. At the end of the experiment, the mice were euthanized after a 16-hr fasting period, and their plasma was collected. Liver and epididymal adipose tissue samples were collected and weighed. Moreover, after 10 weeks of feeding, oral glucose tolerance test was performed. Treatment with SE significantly decreased body weight, adipose tissue weight, plasma glucose, insulin, leptin, and pro-inflammatory cytokines compared with HFD groups, and markedly reduced the impairment of glucose tolerance in obese mice. Furthermore, HFD-induced adipocyte hypertrophy was improved by treatment with SE. Moreover, adipocyte differentiation marker such as proliferator-activated receptor γ was activated by SE treatment. Our findings demonstrate that SE may reduce obesity-induced glucose and insulin tolerance, presumably by the induction of the proliferator-activated receptor γ.

Original Article
Toxicity of repeated 28-day oral administration of acenaphthylene in rats Vol.4, No.6, p.247-259
Shihori Tanabe , Katsumi Kobayashi , Mariko Matsumoto , Hideki Serizawa , Toshime Igarashi , Takashi Yamada , Akihiko Hirose
Released: November 07, 2017
Abstract Full Text PDF[219K]

To assess the toxicity of acenaphthylene, Sprague-Dawley rats were repeatedly administered the chemical via oral gavage at daily doses of 0, 4, 20, or 100 mg/kg/day for 28 days, followed by a 14-day recovery period. Decreases in body weight, food consumption, and body weight gain were observed in males and females in the 100 mg/kg/day group. Additionally, increases in water consumption and urine volume, and decreases in osmolality were observed in both males and females in this group. Moreover, this highest dose was linked to decreases in the reticulocyte percentage and increases in platelet counts in males and females, and females additionally exhibited increases in the hemoglobin concentration, mean corpuscular hemoglobin concentration, and activated partial thromboplastin time. Meanwhile, total cholesterol and phospholipid levels were elevated in males and females treated with 100 mg/kg/day acenaphthylene, with males additionally displaying increased total protein and albumin levels. Increased relative liver weights and changes in liver histopathology were observed in males and females treated with 20 or 100 mg/kg/day acenaphthylene. Additionally, organ weight and/or histopathological changes were observed in the thymus, heart, femoral and sternal bones including bone marrow, urinary bladder, kidneys, spleen, and adrenal gland in both sexes, in the stomach in males, and in the uterus, ovaries, and mesenteric lymph nodes in females in the 100 mg/kg/day group. Some changes exhibited plasticity in the recovery period. Based on these results, the no-observed-effect-level of acenaphthylene after repeated 28-day oral administration was 4 mg/kg/day.