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Mechanisms of Hormonal Carcinogenesis in the p53+/- Hemizygous Knockout Mouse: Studies With Diethylstilbestrol
Paul L. Carmichael
Molecular Toxicology Unit, Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Science, Technology and Medicine, South Kensington, London, SW7 2AZ, United Kingdom, p.carmichael{at}ic.ac.uk
Jeremy J. Mills
Molecular Toxicology Unit, Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Science, Technology and Medicine, South Kensington, London, SW7 2AZ, United Kingdom
Mathew Campbell
Molecular Toxicology Unit, Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Science, Technology and Medicine, South Kensington, London, SW7 2AZ, United Kingdom
Maya Basu
Molecular Toxicology Unit, Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Science, Technology and Medicine, South Kensington, London, SW7 2AZ, United Kingdom
John Caldwell
Molecular Toxicology Unit, Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Science, Technology and Medicine, South Kensington, London, SW7 2AZ, United Kingdom
The 2-year rodentbioassay has long had a central role in determining whether a compound is carcinogenic. It has recently been suggested that the use of 6-month studies in transgenic mice could reduce costs and animal numbers, without impairing the validity of cancer risk assessment. The p53 +/- hemizygous knockout mouse model is phenotypically stable and develops tumors during the 6-month study period only in response to chemical and physical stimuli, showing a high concordance with genotoxic rodent carcinogens. We treated p53+/- mice and wild-type parent strain (C57BL/6J) animals with diethylstilbestrol (DES), 500 µmol/kg i.p. for 4 days. Following sacrifice, DNA was extracted from various tissues and adducts measured by a modifi ed monophosphate version of the 32P-postlabelling assay. Major DES adducts were detected in the liver DNA of DES-treated wild-type mice at a level of 118.7 17.0 (mean SD relative adduct level [RAL]/10 10 nucleotides) compared with 207.7 36.4 in p53 +/-mice. No such adducts were detected in vehicle-treated animals. Total adduct levels, including endogenous I-compound adducts, in wild-type mice were 192.4 17.5 and 311.5 58.6 in p53 +/-animals. These data support the hypothesis that defi cient p53-dependent global genomic repair of DES adducts in p53+/-mice may result in the persistence of exogenous and endogenous DNA adducts that could contribute to earlier carcinogenicity in this model. We also prepared hepatic microsomes from male and female p53+/-and wild-type mice exposed to DES or vehicle. Western blot analysis demonstrated modestly higher basal levels of various cytochrome P450 (CYP) enzymes in the untreated p53 +/-mice compared to the wild-type mice. Furthermore, P450 levels were higher in female DES-treated p53 +/-mice compared to treated wild-type mice. For the p53 +/- knockout mice to be used with confi dence in drug safety studies, a further understanding of the metabolic capacity of these animals is needed.
Key Words: Carcinogenicity testing • Cytochrome P450 • DNA adducts • knockoutmouse model.
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Toxicologic Pathology, Vol. 29, No. 1 suppl,
155-160 (2001)
DOI: 10.1080/019262301753178564
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