title: In vivo evidence for accelerated generation of hydroxyl radicals in liver of Long-Evans Cinnamon (LEC) rats with acute hepatitis.
abstract: The Long-Evans Cinnamon (LEC) rats accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease (WD) and spontaneously develop acute hepatitis with severe jaundice. Although hydroxyl radicals (*OH) have been proposed to be a cause of hepatitis by the accumulation of Cu, it is not clear whether or not *OH can be produced in the liver of hepatitic LEC rats in vivo and also can be involved in the onset of hepatitis. In the present study, *OH production in plasma and liver of hepatitic LEC rats was quantified by trapping *OH with salicylic acid (SA) as 2, 3-dihydroxybenzoic acid (2, 3-DHBA). The ratios of 2, 3-DHBA/SA were significantly higher in plasma and liver of hepatitic LEC rats than those of Wistar rats and LEC rats showing no signs of hepatitis. Furthermore, the ratios of 2, 3-DHBA/SA in plasma and liver of hepatitic LEC rats were almost the same as those of Wistar rats treated orally with CuSO(4) (0.5 mmol/kg) 2 h before acetylsalicylic acid (ASA) injection. We also evaluated the protective effects of D-mannitol (a *OH scavenger) treatment against acute hepatitis in LEC rats. D-mannitol (500 mg/kg) was administered intraperitoneally to 10-week-old LEC rats for 3 weeks. D-mannitol treatment suppressed the increases in serum aspartate aminotransferase activity and total bilirubin concentration. In addition, D-mannitol treatment significantly reduced hepatic mitochondrial lipid peroxidation, which is thought to be important in the pathogenesis of Cu-induced hepatotoxicity. These observations suggest that accelerated generation of *OH catalyzed by free Cu in the liver may, at least in part, play a role in the pathogenesis of acute hepatitis in LEC rats.
authors.affiliation: Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Mizuno
authors.forename: K
authors.initials: K
authors.lastname: Endo
authors.forename: T
authors.initials: T
authors.lastname: Hosokawa
authors.forename: A
authors.initials: A
authors.lastname: Kazusaka
authors.forename: R
authors.initials: R
authors.lastname: Gooneratne
authors.forename: S
authors.initials: S
authors.lastname: Fujita
mesh_terms: D000208:Acute Disease; D000818:Animals; D003300:Copper / Q000378:metabolism; D019327:Copper Sulfate / Q000633:toxicity; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006520:Hepatitis, Animal / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D062385:Hydroxybenzoates / Q000097:blood / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008353:Mannitol / Q000494:pharmacology; D051381:Rats; D020332:Rats, Inbred LEC; D017208:Rats, Wistar; D020156:Salicylic Acid / Q000097:blood / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D062385:Hydroxybenzoates; D017665:Hydroxyl Radical; D008353:Mannitol; C009135:2,3-dihydroxybenzoic acid; D003300:Copper; D019327:Copper Sulfate; D020156:Salicylic Acid