Fundamental Toxicological Sciences

2019 - Vol. 6 No. 8

2019 - Vol. 6

Original Article
Glucosyl hesperidin: safety studies Vol.6, No.8, p.299-317
Shuji Matsumoto , Takaharu Hashimoto , Chie Ushio , Keisuke Namekawa , Alan Blake Richards
Released: November 18, 2019
Abstract Full Text PDF[1M]

Hesperidin is a flavonoid with many nutritional benefits including antioxidant activity in food formulations; however, hesperidin is practically insoluble in water. A commercial enzymatic process has been developed in which a glucose molecule is attached to hesperidin increasing the solubility by approximately 100,000 times. The substance is called glucosyl hesperidin (GH) with the main component being monoglucosyl hesperidin (MGH; 75 to 85%). This paper presents results of OECD-compliant toxicity studies with GH, including 4-week and 13-week sub-chronic toxicity, and teratogenicity studies in rats, and chromosomal aberration and mouse micronucleus formation tests. There were no deaths and no treatment-related adverse effects in the 4-week (highest dose 15,000 ppm) or the 13-week sub-chronic (highest dose 50,000 ppm) studies. There were no statistically significant treatment-related adverse effects on any parameter evaluated. The NOEL in the 4-week study was calculated as 1,280 mg/kg/day in females and 1,206 mg/kg/day for males, and in the 13-week study, the NOEL was 3,428 and 3,084 mg/kg/day, for females and males, respectively. In the teratogenicity study, the NOAEL was 1,000 mg/kg/day of treatment for both dams and fetuses. No genotoxicity was observed in the chromosomal study at 5,000 μg/mL and no micronuclei at 2,000 mg/kg, respectively. The results of these OECD-compliant studies support the safe use of GH as a food and beverage ingredient.

Original Article
Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats as a model for human type 2 diabetes Vol.6, No.8, p.287-297
Tadakazu Takahashi , Chizuru Matsuura , Kaoru Toyoda , Yusuke Suzuki , Naohito Yamada , Akio Kobayashi , Shoichiro Sugai , Kayoko Shimoi
Released: November 18, 2019
Abstract Full Text PDF[4M]

The diabetic state is considered to be one of the risk factors of drug-induced liver injury (DILI) because of the lower levels of glutathione for detoxification by conjugation with drugs. Carbamazepine (CBZ) -induced hepatotoxicity in humans is rare and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are limited. In order to estimate the potential risk of DILI in patients with type 2 diabetes mellitus (T2DM), we investigated the liver injury from CBZ, which is often used in the treatment of painful diabetic neuropathy in diabetic patients, using SD rats and Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats as a model for human T2DM. The SDT fatty rats appropriately mimic the diabetic state in humans and have similar profiles of glucose metabolism, hepatic function tests and glutathione synthesis to those in patients with T2DM. Short-term oral dosing with CBZ to the SDT fatty rats revealed that liver injury was detected in the SDT fatty rats but not in the SD rats and the difference was considered to be due to lower hepatic detoxification of the metabolites of CBZ by depleted hepatic glutathione synthesis. In conclusion, the potential for CBZ to induce liver injury is considered to be higher in diabetic patients than in non-diabetic humans.

Letter
Transmission electron microscopy of the benzbromaroneinduced change in mitochondrial morphology in HepG2 cells Vol.6, No.8, p.281-286
Tomoyuki Sato , Akinori Takemura , Yugo Ikeyama , Yuriko Sakamaki , Ayako Mimata , Haruyo Aoyagi , Hideki Aizaki , Shuichi Sekine , Kousei Ito
Released: October 25, 2019
Abstract Full Text PDF[4M]

Drug-induced mitochondrial dysfunction can lead to severe adverse effects. Accordingly, new in vitro assay systems for assessing mitochondrial-related toxicity are required. Current systems evaluate drug-induced mitochondrial dysfunction based on cell death. However, if mitochondria are damaged without cell death, these methods run the risk of overlooking toxic or dangerous compounds. To solve this problem, we attempted to measure morphological changes semi-quantitatively by transmission electron microscopy and to detect subtle changes in mitochondrial function. To this end, we exposed HepG2 cells cultured in galactose-containing medium to benzbromarone (BBR), which impairs mitochondrial function. After 24 hr of BBR exposure, we compared the rate of cell death between galactose and glucose cultures. Before the onset of cell death, BBR increased the ratio of damaged mitochondria to a greater extent in galactose-cultured than glucose-cultured HepG2 cells. Our results suggested that this new in vitro assay system could detect mitochondrial-related toxicity before the onset of cell death.