title: Evaluation of hepatic damage by reactive metabolites--with consideration of circadian variation of murine hepatic glutathione levels.
abstract: Generally, reactive metabolites are detoxified by conjugation with glutathione (GSH). A GSH-depleted model was prepared by administering L-buthionine-(S,R)-sulfoximine (BSO), which can be used to detect hepatic damage by reactive metabolites. However, BSO may cause adverse effects on other organs, such as renal damage by reactive metabolites because it depletes GSH in the whole body. The present study was designed to examine whether it was possible to specifically detect hepatic damage by reactive metabolites without reducing renal GSH levels by administering BSO in a time course when hepatic GSH levels are naturally reduced. Male BALB/c mice were administered reverse osmosis (RO) water or 20 mmol/l BSO in drinking water for 4 days. Subsequently, animals in the RO water group were orally administered 500 mg/kg acetaminophen (APAP) at 9:00 or 15:00 and in the BSO group at 9:00 for 4 days. As a result, severe hepatic damage and necrosis of the renal proximal tubules were observed in the BSO/APAP administration at 9:00 group, and all animals died on 1 or 2 days after APAP administration. Hepatic damage was clearly increased in the RO water/APAP administration at 15:00 group compared with the RO water/APAP administration at 9:00 group. However, renal damage and deaths were not observed. This BSO administration model may detect renal damage induced by reactive metabolites. Using an administration time course, whereby hepatic GSH levels were naturally reduced, hepatic damage by reactive metabolites can be detected without secondary renal effects.
authors: Fukushima Research Laboratories, R&D Department, TOA EIYO LTD.
authors: Koji
authors: K
authors: Mori
authors: Atsushi
authors: A
authors: Kumano
authors: Toshihisa
authors: T
authors: Kodama
authors: Shigeyuki
authors: S
authors: Takiguchi
authors: Naomi
authors: N
authors: Takano
authors: Kohei
authors: K
authors: Kumada
authors: Kana
authors: K
authors: Hatao
authors: Takashi
authors: T
authors: Kimura
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D009995:Osmosis / Q000502:physiology; D013997:Time Factors; D014867:Water / Q000008:administration & dosage
chemical_list: D014867:Water; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D005978:Glutathione