Modifying Effects of Flumequine on Dimethylnitrosamine-Induced Hepatocarcinogenesis in Heterozygous p53 Deficient CBA Mice.

Abstract

Flumequine (FL), a quinolone-antibiotic used for veterinary treatment of infections, was found to elicit hepatocellular tumors in a conventional 18-month carcinogenicity study in mice, and hepatocellular necrosis-regeneration cycle was considered to be a possible underlying mechanism. In order to clarify whether FL has any modifying effects on development of hepatocellular proliferation, groups of heterozygous p53 deficient CBA mice [p53(+/-) mice], sensitive to genotoxic carcinogen, of both sexes and their wild-type littermates [p53(+/+) mice] were fed diet containing 4,000 or 0 ppm FL for 26 weeks after an intraperitoneal injection of 5 or 0 mg/kg body weight of dimethylnitrosamine (DMN). Higher incidences of hepatocellular foci were observed in animals receiving FL, with or without DMN-initiation, than in the corresponding control groups in both p53(+/-) and p53(+/+) mice. Incidences and multiplicities of foci were generally similar in p53(+/-) and p53(+/+) mice, but, in the DMN+FL group, multiplicity of foci and their PCNA labeling indices were greater in p53(+/-) mice. There were also small numbers of hepatocellular adenomas and carcinomas in the DMN+FL group of p53(+/-) mice, hepatocellular adenoma in the FL alone group of p53(+/-) mice, and hepatocellular adenomas in the DMN+FL group of p53(+/+) mice. Induction of hepatocellular tumors in these mice within a relatively short period strongly suggests that mechanisms such as direct or indirect damage to DNA might be responsible for the hepatocarcinogenesis of FL.