Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans

Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in humans. Selenium (Se) and glutathione (GSH) have a crucial role for the hepatoprotective effect against reactive metabolites or oxidative damage leading to DILI. The hepatoprotective capacity related to Se and GSH in rodents is considered to be superior compared to the capacity in humans. Therefore, we hypothesize that Se/GSH-depleted rats could be a sensitive animal model to predict DILI in humans. In this study, Se-deficiency is induced by feeding a Se-deficient diet and GSH-deficiency is induced by l-buthionine-S,R-sulfoxinine treatment via drinking water. The usefulness of this animal model is validated using flutamide, which is known to cause DILI in humans but not in intact rats. In the Se/GSH-depleted rats from the present study, decreases in glutathione peroxidase-1 protein expression and GSH levels and an increase in malondialdehyde levels in the liver are observed without any increase in plasma liver function parameters. Five-day repeated dosing of flutamide at 150 mg/kg causes hepatotoxicity in the Se/GSH-depleted rats but not in normal rats. In conclusion, Se/GSH-depleted rats are the most sensitive for detecting flutamide-induced hepatotoxicity in all the reported animal models

DELP 1985年度日本海研究航海報告 : VI. DELP 85, Leg IIおよびKT85-15航海で採集された堆積物試料について

Surface sediments samples which are distributed around the area in the eastern and southern parts of the Japan Sea were taken at 28 localities during the DELP85 and KT85-15 cruises. The fine-grained sediments that show a prominent color variation were distributed in the eastern part (the Mogami Trough region). This color variation may be effected by volcanic activities with gas eruption on the sea floor. The Yamato Rise in the southern part is an outcropped area of rocks. The foraminiferal sand that contains shell fragments, etc. are distributed on the Yamato Rise.DELP85およびKT85-15航海を通じ,日本海東部(最上舟状海盆周辺)および日本海南部(大和堆周辺)において28ケ所で表層堆積物試料を採集した.最上舟状海盆周辺には色の変化に富む細粒堆積物が存在し,海底火山活動に伴うガス噴出の影響を受けていると考えられる.また最上深海チャネルを通じて運搬されたと考えられる混質乱泥流堆積物が認められる.大和堆は北大和舟状海盆周辺を除き露岩域である.大和堆上には貝殻片等を含む有孔虫砂が分布する