title: Drug-induced hepatotoxicity test using gamma-glutamylcysteine synthetase knockdown rat.
abstract: Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem for drug development. It is generally known that DILI is mainly caused by hepatic glutathione (GSH) depletion. The glutathione S-transferase activity of rodent is higher than that of human, which could make the prediction of DILI more difficult. Recently, we reported that an experimental rat model of GSH-depletion displayed high susceptibility to acetaminophen-induced hepatotoxicity. To deplete GSH, we used an adenovirus vector with short hairpin RNA against gamma-glutamylcysteine synthetase heavy chain subunit (AdGCSh-shRNA). In this study, we further investigated the usefulness of this rat model for determining drug-induced sensitive acute and subacute toxicity. Rats were administered diclofenac and flutamide which have been reported as idiosyncratic hepatotoxic drugs. In the acute (6 or 24h) or subacute (7 days) toxicity tests, rats were administered the drugs once or once a day for a week, respectively. Plasma biochemical markers for hepatotoxicity were measured. The 6 and 24h toxicity test of diclofenac, and the 24h and 7 days toxicity tests of flutamide showed significant ALT elevations. Additionally, the 24h toxicity test of flutamide showed a slight bilirubin elevation, and histological hepatotoxicity. The 7 days toxicity test of flutamide also demonstrated histological hepatotoxicity. In conclusion, this rat model would contribute to evaluating acute and subacute DILI in preclinical drug development.
authors.affiliation: Division of Pharmaceutical Sciences, Faculty of Pharmaceutical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.forename: Sho
authors.initials: S
authors.lastname: Akai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hosomi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D004008:Diclofenac / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000633:toxicity*; D020868:Gene Silencing; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D008297:Male; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000726:Androgen Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D005485:Flutamide; D005721:Glutamate-Cysteine Ligase