Organ-specific genotoxicity of the potent rodent bladder carcinogens o-anisidine and p-cresidine

Sasaki, Yu; Nishidate, Emi; Su, Ying Quan; Matsusaka, Naonori; Tsuda, Shuji; Susa, Nobuyuki; Furukawa, Yoshinori; Ueno, Shunji

doi:10.1016/s1383-5718(97)00183-6

Cited by 25 publications

(7 citation statements)

References 21 publications

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“…p -Cresidine has been reported previously to be inactive in an assay measuring DNA single strand breaks (Ashby et al 1991). However, a COMET assay on CD-1 male mouse liver, lung, kidney, brain, and bone marrow after a single dose of p -cresidine at 595 mg/kg produced DNA damage, although only in bladder mucosa (Sasaki et al 1998). In a COMET assay using hepatocytes in vitro, clofibrate caused DNA strand breaks at concentrations of 50 μM and higher, perhaps caused by the acyl glucuronide of clofibrate (Ghaoui et al 2003).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

et al. 2005

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This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

et al. 2005

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“…This could be examined by assessment of DNA adduct formation. p -Cresidine is only weakly active or negative in most genotoxicity assays (Ashby et al, 1991), but did produce DNA damage in mouse bladder mucosa measured by the single cell gel electrophoresis (Comet) assay (Sasaki et al, 1998).…”

Section: Rodent Nasal Carcinogensmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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“…The chemical induces chromosomal aberrations in Chinese hamster ovary cells,17 gene mutations in mouse lymphoma cells18 and intrachromosomal recombinations in Saccharomyces cerevisiae 19. A statistically significant DNA damage in urinary bladder of CD‐1 mice exposed to o ‐anisidine determined by the single‐cell gel electrophoresis (Comet) assay was detected 20. Moreover, Ashby et al 14, 21.…”

mentioning

confidence: 99%

Identification of a genotoxic mechanism for the carcinogenicity of the environmental pollutant and suspected human carcinogeno-anisidine

et al. 2005

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2-methoxyaniline (o-anisidine) is an industrial and environmental pollutant and a bladder carcinogen for rodents. The mechanism of its carcinogenicity was investigated with 2 independent methods, 32 P-postlabeling and 14 C-labeled o-anisidine, to show that o-anisidine binds covalently to DNA in vitro after its activation by human hepatic microsomes. We also investigated the capacity of o-anisidine to form DNA adducts in vivo. Rats were treated i.p. with oanisidine (0.15 mg/kg daily for 5 days) and DNA from several organs was analyzed by 32 P-postlabeling. Two o-anisidine-DNA adducts, identical to those found in DNA incubated with o-anisidine and human microsomes in vitro, were detected in urinary bladder (4.1 adducts per 10 7 nucleotides), the target organ, and, to a lesser extent, in liver, kidney and spleen. These DNA adducts were identified as deoxyguanosine adducts derived from a metabolite of o-anisidine, N-(2-methoxyphenyl)hydroxylamine. This metabolite was identified in incubations with human microsomes. With 9 human hepatic microsomal preparations, we identified the specific CYP catalyzing the formation of the o-anisidine metabolites by correlation studies and by examining the effects of CYP inhibitors. On the basis of these analyses, oxidation of o-anisidine was attributed mainly to CYP2E1. Using recombinant human CYP (in Supersomes) and purified CYPs, the participation of CYP2E1 in o-anisidine oxidation was confirmed. In Supersomes, CYP1A2 was even more efficient in oxidizing o-anisidine than CYP2E1, followed by CYP2B6, 1A1, 2A6, 2D6 and 3A4. The results, the first report on the potential of the human microsomal CYP enzymes to activate o-anisidine, strongly suggest a carcinogenic potential of this rodent carcinogen for humans. ' 2005 Wiley-Liss, Inc.

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Organ-specific genotoxicity of the potent rodent bladder carcinogens o-anisidine and p-cresidine

Cited by 25 publications

References 21 publications

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Identification of a genotoxic mechanism for the carcinogenicity of the environmental pollutant and suspected human carcinogeno-anisidine

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Organ-specific genotoxicity of the potent rodent bladder carcinogens o-anisidine and p-cresidine

Cited by 25 publications

References 21 publications

Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Identification of a genotoxic mechanism for the carcinogenicity of the environmental pollutant and suspected human carcinogeno-anisidine

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Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse