- 著者
- Satoshi Tamai Takuma Iguchi Noriyo Niino Kei Mikamoto Ken Sakurai Ayako Sayama Hitomi Shimoda Wataru Takasaki Kazuhiko Mori
- 出版者
- The Japanese Society of Toxicology
- 雑誌
- The Journal of Toxicological Sciences (ISSN:03881350)
- 巻号頁・発行日
- vol.42, no.1, pp.73-84, 2017-02-01 (Released:2017-01-07)
- 参考文献数
- 44
- 被引用文献数
- 6 8
Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.
- 著者
- Ayako SAYAMA Keiko OKADO Masako IMAOKA Yusuke YOKOUCHI Toshimasa JINDO Wataru TAKASAKI
- 出版者
- 日本毒性病理学会
- 雑誌
- Journal of Toxicologic Pathology (ISSN:09149198)
- 巻号頁・発行日
- pp.2013-0044, (Released:2014-02-05)
- 被引用文献数
- 1 1
A nine-year-old male beagle dog had a white spherical mass in the subcutis of the left lumbar region. Microscopically, spindle to oval cells diffusely proliferated in the fibrous and myxoid stroma. Many neoplastic cells showed rhabdoid features or vacuolated cytoplasm. Immunohistochemically, the neoplastic cells were positive for vimentin and S100 and partly positive for neuron-specific enolase and glial fibrillary acidic protein but were negative for von Willebrand factor, desmin and α-smooth muscle actin. Ultrastructurally, the neoplastic cells had abundant cytoplasmic processes and desmosome-like structures. Cytoplasmic inclusions of rhabdoid-featured cells in HE sections were composed of aggregates of intermediate filaments, and cytoplasmic vacuoles were identified as an invagination of cytoplasm. Although malignant peripheral nerve sheath tumor was suggested according to these results, the present case was diagnosed as a soft tissue sarcoma with rhabdoid features due to a lack of identification of the basal lamina under electron microscopy.