Fundamental Toxicological Sciences

2018 - Vol. 5 No. 1

2018 - Vol. 5

Original Article
Increased hepatic triglyceride level induced by a glucokinase activator in mice Vol.5, No.1, p.13-20
Junichi Namekawa , Mari Yasui , Atsuko Katayanagi , Mitsuyuki Shirai , Fumitoshi Asai
Released: February 06, 2018
Abstract Full Text PDF[1M]

Glucokinase (GK) is an enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate, and plays an important role in maintaining glucose homeostasis by regulating secretion of insulin from pancreatic β-cells and glucose metabolism in the liver. Recently, GK activators are expected as a novel therapeutic agent for Type 2 diabetes mellitus (T2DM). However, the increase in plasma triglyceride (TG) levels is one of the major issues for the development of GK activators. In this study, we evaluated the effects of the GK activator GKA50 on the plasma and hepatic TG in mice. Male CD-1 mice received a single oral dose of vehicle or GKA50 (15, 30, or 60 mg/kg), and plasma glucose and insulin levels were measured. Next, CD-1 mice received oral doses of vehicle or GKA50 (20 or 60 mg/kg) once daily for 4 days, and clinical signs, body weight, food consumption, blood chemistry, and hepatic TG were evaluated. In the single oral dose study, dose-dependent decrease in plasma glucose levels and increase in plasma insulin levels were observed. In the 4-day repeated dose study, there were no treatment-related changes in clinical signs, body weight, food consumption, or plasma TG levels. In the 60 mg/kg group, a significant increase in the hepatic TG level was observed. Additionally, the detailed analysis of TG species composition revealed marked increases in TGs mainly composed of 18:1 fatty acids. This study revealed that GKA50 enhanced insulin secretion and hepatic glucose utilization, and increased hepatic TGs, which were mainly composed of 18:1 fatty acids.

Original Article
A 28-day repeated oral-dose toxicity study of insecticide synergist N-(2-ethylhexyl)-1-isopropyl-4-methylbicyclo[2.2.2] oct-5-ene-2,3-dicarboximide in rats Vol.5, No.1, p.1-11
Mariko Matsumoto , Masatoshi Furukawa , Katsumi Kobayashi , Takako Iso , Toshime Igarashi , Takashi Yamada , Akihiko Hirose
Released: January 19, 2018
Abstract Full Text PDF[254K]

N-(2-Ethylhexyl)-1-isopropyl-4-methylbicyclo[2.2.2]oct-5-ene-2,3-dicarboximide (Synepirin 500; CAS: 13358-11-7) is used as a synergist, a chemical that makes pesticide ingredients more effective. People can be exposed to Synepirin 500 by using insecticides containing this chemical or from residues in food. The Japanese government chose this chemical as a target substance in its existing chemical testing program. Crl:CD(SD) rats were administered 0, 40, 200, and 1000 mg/kg/day Synepirin 500 by gavage for 28 days, followed by a 14 day recovery period. Diarrhea or soft feces were observed in both sexes at 1000 mg/kg/day. Absolute and/or relative liver weights significantly increased at ≥ 40 mg/kg/day in females and at ≥ 200 mg/kg/day in males. Absolute and/or relative thyroid weights significantly increased in both sexes at 1000 mg/kg/day. These changes were still significant at the end of the recovery period in females. Significantly prolonged prothrombin time and activated partial thromboplastin time were observed in males receiving ≥ 40 mg/kg/day. Histopathological changes in the liver and thyroid were observed in both sexes at 1000 mg/kg/day. On the basis of the effects on the liver, the level of the lowest observed adverse effect from repeated doses of Synepirin 500 was judged to be 40 mg/kg/day for rats.