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

International Journal of Cancer. Journal International Du Cancer
Annette M KraisVolker M Arlt

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)...Continue Reading

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Citations

Jul 2, 2016·Environmental and Molecular Mutagenesis·Derek T BernackiStephen D Dertinger
Dec 3, 2016·Toxicology Letters·Juliana Yumi SakitaVinicius Kannen
Feb 11, 2020·Environmental and Molecular Mutagenesis·Shuchang TianStephen D Dertinger
Oct 12, 2019·Archives of Toxicology·Mateja SborchiaVolker M Arlt
Dec 11, 2019·International Journal of Molecular Sciences·Mateja SborchiaVolker M Arlt
Apr 1, 2021·Seminars in Cancer Biology·Yanqing Liu, Wei Gu

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Methods Mentioned

BETA
gene knock‐out

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