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Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice
Yoko Kashida1, Yu F Sasaki, Koh-ichi Ohsawa
1Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
Abstract:
In order to elucidate the tumor-initiating potential of flumequine (FL) in the liver, male C3H mice were given dietary administration of 4000 ppm FL throughout the study or for 2 weeks at the initiation stage, and then received 2 intraperitoneal injections of D-galactosamine (Gal) at weeks 2 and 5, with or without 500 ppm phenobarbital (PB) in their drinking water for 13 weeks to provide tumor-promoting effects. Hepatocellular foci were observed in 2 out of 8 and 6 out of 7 animals in the FL/PB + Gal and FL/FL + Gal groups, respectively. In addition, in an alkaline single-cell gel electrophoresis (comet) assay that was performed using adult, infant, or partial hepatectomized male ddY mice to evaluate the potential of FL at 500 mg/kg or less, to act as a DNA damaging agent. FL induced dose-dependent DNA damage in the stomach, colon, and urinary bladder of adult mice at 3 h but not at 24 h after its administration. Similarly, DNA damage was noted in the regenerating liver and the livers of infant mice at the 3 h time point. Furthermore, in in vitro assays that were conducted to investigate the potential of FL to inhibit eukaryotic topoisomerase II, which is responsible for the double-strand DNA breakage reaction as well as bacterial gyrase, inhibitory effects of FL on topoisomerase II were high relative to the influence on bacterial gyrase. The results of our studies thus strongly suggest that FL has initiating potential in the livers of mice that is attributable to its induction of DNA strand breaks.
Insights
Flumequine (FL) initiates liver tumors in mice by causing DNA strand breaks. This DNA damage was observed in multiple organs and linked to FL
Area of Science:
- Hepatocarcinogenesis Research
- Genotoxicity Studies
- Drug Safety Evaluation
Background:
- Flumequine (FL) is an antibiotic with potential tumor-initiating properties.
- Understanding the genotoxic and carcinogenic mechanisms of FL is crucial for drug safety.
- Previous studies have not fully elucidated FL's tumor-initiating potential in the liver.
Purpose of the Study:
- To investigate the tumor-initiating potential of flumequine (FL) in the liver.
- To evaluate FL's capacity to induce DNA damage in various tissues.
- To determine the mechanism by which FL may initiate liver tumors.
Main Methods:
- Male C3H mice were administered FL and D-galactosamine (Gal), with or without phenobarbital (PB), to assess liver tumor initiation and promotion.
- Alkaline single-cell gel electrophoresis (comet assay) was used to evaluate FL-induced DNA damage in adult, infant, and regenerating mouse livers, as well as other tissues.
- In vitro assays assessed FL's inhibitory effects on eukaryotic topoisomerase II and bacterial gyrase.
Main Results:
- Hepatocellular foci, indicative of tumor initiation, were observed in mice exposed to FL and tumor promoters.
- FL induced dose-dependent DNA strand breaks in the stomach, colon, and urinary bladder of adult mice.
- DNA damage was also detected in the regenerating liver and infant mouse livers, and FL showed higher inhibition of eukaryotic topoisomerase II than bacterial gyrase.
Conclusions:
- Flumequine (FL) demonstrates tumor-initiating potential in mouse livers.
- FL's hepatocarcinogenicity is attributed to its ability to induce DNA strand breaks.
- The findings highlight the genotoxic risk associated with flumequine exposure.