Metabolic activation of 2‐amino‐1‐methyl‐6‐phenylimidazo [4,5‐b]pyridine and DNA adduct formation depends on p53: Studies in Trp53(+/+),Trp53(+/−) and Trp53(−/−) mice |
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| Authors: | Annette M. Krais Ewoud N. Speksnijder Joost P.M. Melis Rajinder Singh Anna Caldwell Gonçalo Gamboa da Costa Mirjam Luijten David H. Phillips Volker M. Arlt |
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| Affiliation: | 1. Analytical and Environmental Sciences Division, MRC‐PHE Centre for Environment and Health, King's College London, London, United Kingdom;2. Annette M. Krais current address is: Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden;3. Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, MA, The Netherlands;4. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands, RC;5. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom;6. Mass Spectrometry Facility, King's College London, London, United Kingdom;7. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR |
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| Abstract: | The expression of the tumor suppressor p53 can influence the bioactivation of, and DNA damage induced by, the environmental carcinogen benzo[a]pyrene, indicating a role for p53 in its cytochrome P450 (CYP)‐mediated biotransformation. The carcinogen 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), which is formed during the cooking of food, is also metabolically activated by CYP enzymes, particularly CYP1A2. We investigated the potential role of p53 in PhIP metabolism in vivo by treating Trp53(+/+), Trp53(+/?) and Trp53(?/?) mice with a single oral dose of 50 mg/kg body weight PhIP. N‐(Deoxyguanosin‐8‐yl)‐2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP‐C8‐dG) levels in DNA, measured by liquid chromatography‐tandem mass spectrometry, were significantly lower in liver, colon, forestomach and glandular stomach of Trp53(?/?) mice compared to Trp53(+/+) mice. Lower PhIP‐DNA adduct levels in the livers of Trp53(?/?) mice correlated with lower Cyp1a2 enzyme activity (measured by methoxyresorufin‐O‐demethylase activity) in these animals. Interestingly, PhIP‐DNA adduct levels were significantly higher in kidney and bladder of Trp53(?/?) mice compared to Trp53(+/+) mice, which was accompanied by higher sulfotransferase (Sult) 1a1 protein levels and increased Sult1a1 enzyme activity (measured by 2‐naphthylsulfate formation from 2‐naphthol) in kidneys of these animals. Our study demonstrates a role for p53 in the metabolism of PhIP in vivo, extending previous results on a novel role for p53 in xenobiotic metabolism. Our results also indicate that the impact of p53 on PhIP biotransformation is tissue‐dependent and that in addition to Cyp1a enzymes, Sult1a1 can contribute to PhIP‐DNA adduct formation. |
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| Keywords: | tumor suppressor p53 heterocyclic aromatic hydrocarbon PhIP carcinogen metabolism DNA adduct formation cytochrome P450 sulfotransferases mouse model mass spectrometry |
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