title: Hepatotoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice.
abstract: It has been reported that flumequine (FLU) induces hepatic tumors in mice when given orally for 18 months. We investigated possible underlying mechanisms using a two-stage mouse hepatocarcinogenesis model. After initiation with a single intraperitoneal injection of 100 mg/kg body weight diethylnitrosamine (DEN) or saline, male CD-1 mice were given 4000 ppm FLU in the diet or 500 ppm phenobarbital (PB) in drinking water for 9, 19, 24 or 30 weeks. Toxicity, evidenced by centrilobular swollen and polar hepatocytes with fatty droplets, infiltration of inflammatory cells and increased numbers of mitosis in hepatocytes, was apparent in the livers of mice treated with FLU at all time points, but its severity declined towards the termination. FLU did not induce cytochrome P-450 enzymes such as 1A1, 2B1 and 3A2 as assessed immunohistochemically, while positive expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was increased in hepatocytes of both DEN + FLU and FLU groups compared with the relevant controls. In animals given PB, eosinophilic swelling of hepatocytes was prominent, and the hepatocytes showed strongly positive reactions for CYP 1A1 and 3A2. Altered cell foci were induced in the livers of FLU-treated animals both with and without DEN initiation, especially the former, and their development paralleled the degree of hepatic toxicity. These results suggest that FLU hepatocarcinogenicity in mice is dependent on hepatotoxic damage and consequently increased cell proliferation. Oxidative damage to DNA may also be a crucial factor.
authors.affiliation: Department of Pathology, Sasaki Institute, Tokyo, Japan. amaekawa@sasaki.or.jp
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Miyajima
authors.forename: K
authors.initials: K
authors.lastname: Shiraki
authors.forename: J
authors.initials: J
authors.lastname: Ando
authors.forename: K
authors.initials: K
authors.lastname: Kudoh
authors.forename: D
authors.initials: D
authors.lastname: Nakae
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Maekawa
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004052:Diethylnitrosamine; D024841:Fluoroquinolones; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011807:Quinolizines / Q000633:toxicity*; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D018809:Proliferating Cell Nuclear Antigen; D011807:Quinolizines; D004052:Diethylnitrosamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C022657:steroid hormone 6-beta-hydroxylase; D003849:Deoxyguanosine; C012976:flumequine; D010634:Phenobarbital