Liver initiation activity of norfloxacin but not nalidixic acid, pipemidic acid, and ciprofloxacin on in vivo short-term liver initiation assay in rats

Itoh, Tadashi; Moto, Mitsuyoshi; Takahashi, Miwa; Sakai, Hiroki; Mitsumori, Kunitoshi

doi:10.1016/j.tox.2006.02.019

Cited by 9 publications

(19 citation statements)

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“…These results suggest that under the conditions in the present study, the initiation activity of NFLX does not result in the induction of hepatocellular tumors and that the initiation activity of NFLX is extremely weak. Taking into account the results of the previous in vivo short-term liver initiation assay in rats (Itoh et al, 2006b), it appears that the hepatocellular preneoplastic lesions which were initiated with NFLX does not progress to hepatocellular tumors by promotion treatment of PB alone for 51 weeks. Only one rat in the 750 mg/kg group in Experiment 3 showed a macroscopic hepatic tumor that was histologically diagnosed as hepatocellular adenoma.…”

Section: Discussionmentioning

confidence: 94%

“…Additionally, we performed the in vitro micronucleus (MN) test with four quinolones (NA, PPA, CPFX, and NFLX) and reported that NFLX-induced SSBs resulted in chromosome aberrations (Itoh et al, 2006a). The results of an in vivo short-term liver initiation assay of rats with four quinolones (NA, PPA, CPFX, and NFLX) demonstrated that NFLX increased the mean number and area of glutathione S-transferase placental form (GST-P) positive foci that are regarded as hepatocellular preneoplastic lesions (Itoh et al, 2006b). These results strongly indicate that NFLX causes DNA damage, and even the administration of a single oral dose of NFLX in partially hepatectomized rats is adequate for the initiation activity in the liver.…”

Section: Introductionmentioning

confidence: 99%

“…To examine whether the initiation activity of NFLX which induced hepatocellular preneoplastic lesions in our previous short-term study (Itoh et al, 2006b) results in the induction of hepatocellular tumors, in the present study, rats were subjected to two-thirds partial hepatectomy (PH) prior to initiation treatment with NFLX; this was followed by long-term promotion treatment with phenobarbital (PB).…”

Section: Introductionmentioning

confidence: 99%

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The initiation activity of norfloxacin does not result in the induction of hepatocellular tumors in rats

et al. 2007

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The initiation activity of norfloxacin does not result in the induction of hepatocellular tumors in rats

et al. 2007

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“…This observation seems to contradict to the negative responses in the two-step carcinogenicity studies with both species. Considering that the modiˆed two-step carcinogenesis study where animals receive a chemical after partial hepatectomy was recently conducted to detect more appropriately weak initiating activity of a chemical (20), no initiating activity of kojic acid in mice and rats previously reported (12,13) might not be evaluated appropriately. Therefore, it would be premature to conclude that its hepatic genotoxicity detected by the comet assay in both species contradicts to negative responses in the two-step carcinogenicity studies with both species.…”

Section: Discussionmentioning

confidence: 99%

In vivo Genotoxic Potential of Kojic Acid in Rodent Multiple Organs Detected by the Comet Assay

Kawaguchi

Nakamura

Honda

et al. 2008

Genes and Environment

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Kojic acid has been used for skin whitening as a cosmetic agent. Kojic acid is believed to be hepatocarcinogenic in mice. We conducted the comet assay in mouse and rat multiple organs to evaluate its in vivo genotoxic potential. Kojic acid induced dose-dependent DNA damage in ddY mouse stomach and liver and in Wistar rat stomach, liver, lung, and bone marrow after a single gavage administration at ≦1000 mg/kg. Its hepatic genotoxicity detected by the comet assay seems to contradict to absence of its hepatic tumor initiating activity revealed by the two-step carcinogenesis studies with mice and rats. However, considering the possibility that the sensitivity of the two-step carcinogenesis studies performed are not high enough to detect weak initiating activity of a chemical, it would be premature to conclude that its hepatic genotoxicity contradicts to the absence of initiating activity. In mice fed a diet containing 3% kojic acid for up to 10 days, DNA migration increased in the stomach after feeding for 2 days but it did not increased after feeding for 1 day and ≧4 days. In the colon, DNA migration after feeding of 3% kojic acid for 2 days was higher than the control values, but this increase was not statistically signiˆcant. In the stomach and colon, any statistically signiˆcant increases in DNA migration were not observed after feeding of 1.5% kojic acid. In the liver, DNA migration increased with feeding period and the increases after feeding of 3% and 1.5% kojic acid for ≧4 days and 6 days, respectively, were statistically signiˆcant. Our present results suggested good correlation between hepatocarcinogenicity of kojic acid and increasing tendency of its hepatic genotoxicity with dosing period when it is given to mice continuously in the diet.

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“…Partial hepatectomy (PH) strongly induces hepatocyte proliferation and is widely utilized as a cell proliferation stimulus in the medium-term liver initiation assay model [19,25,38,46]. However, performing PH involves certain problems.…”

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confidence: 99%

Detection of Initiation Activity of 1,2-Dimethylhydrazine in in vivo Medium-Term Liver Initiation Assay Ssytem using 4-Week-Old Rats without Hepatocellular Proliferative Stimuli during the Test Chemical Treatment Period

Asaoka

Sakai

Hirata

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. We have developed an in vivo medium-term liver initiation assay system to detect initiation activities of chemicals on multiorgan carcinogenesis. However, cell proliferation stimuli during the test chemical treatment period, required in the previously used assay models using adult rats, are laborious; moreover, those cause decrease of hepatic metabolic enzymes and psychological and physical discomfort to animals resulting in inaccurate interpretation. Therefore, we investigated the utility of another in vivo medium-term liver initiation assay model using 4-week-old rats without the cell proliferation stimuli. In this study, we confirmed that 4-week-old and 4.5-week-old male rats have high hepatocyte proliferation activity and similar enzyme activities of hepatic Cytochrome P450 subtypes as compared with 8-week-old male rats. Next, the in vivo medium-term liver initiation assay model using 4-week-old rats without cell proliferation stimuli was evaluated for the detection of the initiation activity of 1,2-dimethylhydrazine (DMH), which is a well-known genotoxic carcinogen. Four-week-old rats were orally administered DMH (single dose, 4 or 16 mg/kg; or 4-day repeat, 1 or 4 mg/kg); subsequently, these rats were treated promotion treatment consisted of administration of 2-acetylaminofluorene and carbon tetrachloride. Four weeks after the first DMH administration, the glutathione S-transferase placental form (GST-P)-positive foci induced by DMH in the liver was measured immunohistochemically. The inductions of GST-P-positive foci in all DMH-treated groups were dose-dependent, duration-dependent and significantly higher than that in non-DMH-treated group. From these results, our assay model was detected the initiation activity of DMH simply, and would be useful to evaluate the carcinogenicity of chemicals.KEY WORDS: 1,2-dimethylhydrazine (DMH)Introduction, carcinogenesis, GST-P-positive cell foci, liver, rat.J. Vet. Med. Sci. 72(1): 43-53, 2010 Several models are available today for studying the mechanism and activity of carcinogenesis in vivo, most comprising multistage studies involving initiation, promotion, and progression [15]. In vivo medium-term carcinogenic assays based on the multi-stage carcinogenesis hypothesis have been developed in order to bridge the gap between long-term in vivo carcinogenicity studies and shortterm in vitro screening tests [16,22,47,53]. The Ito model for the detection of the promotion activity in the liver has already been validated using a long list of chemicals and is widely used to detect the promotion activities of chemicals [23,24]. Initiation is also a key event in multi-stage carcinogenesis, resulting from complicated processes in vivo [17]. Therefore, an in vivo medium-term liver initiation assay model has also been developed to detect initiation activity of chemicals, and 26 well-known chemicals have been evaluated [38].The medium-term liver initiation assay model could detect genotoxic carcinogens, regardless of the target organ, with reference to the induction o...

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Liver initiation activity of norfloxacin but not nalidixic acid, pipemidic acid, and ciprofloxacin on in vivo short-term liver initiation assay in rats

Cited by 9 publications

References 20 publications

The initiation activity of norfloxacin does not result in the induction of hepatocellular tumors in rats

The initiation activity of norfloxacin does not result in the induction of hepatocellular tumors in rats

In vivo Genotoxic Potential of Kojic Acid in Rodent Multiple Organs Detected by the Comet Assay

Detection of Initiation Activity of 1,2-Dimethylhydrazine in in vivo Medium-Term Liver Initiation Assay Ssytem using 4-Week-Old Rats without Hepatocellular Proliferative Stimuli during the Test Chemical Treatment Period

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