Effect of CYP1A2 deficiency on heterocyclic amine DNA adduct levels in mice

doi:10.1016/S0278-6915(02)00110-2

Food and Chemical Toxicology

Volume 40, Issue 10, October 2002, Pages 1529-1533

https://doi.org/10.1016/S0278-6915(02)00110-2 Get rights and content

Abstract

The contribution of CYP1A2 to the formation of DNA adducts of the cooked meat-derived heterocyclic amines (HCAs) 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined in CYP1A2-null (knock-out, KO) and wild-type (WT) mice. IQ (25 mg and 75 mg/kg) and PhIP (150 mg/kg) were administered by gavage to mice and DNA adduct levels in liver, kidney, mammary gland and colon were examined by the ³²P-postlabeling assay. Three hours after either dose of IQ, adducts levels in liver and kidney of KO mice were 20–30% of the levels in WT mice, a difference that was statistically significant (Student's t-test, P<0.05). In the colon, adduct levels in KO mice were significantly lower than in the WT mice only at the lowest dose of IQ (1.6±0.6 vs 4.6±0.7, respectively, relative adduct labeling (RAL)×10⁸, mean±S.E.M., n=3–5 mice). In the mammary gland, however, there was no difference in IQ–DNA adduct levels in KO and WT mice at either dose of IQ. Three hours after dosing with PhIP, PhIP–DNA adduct levels were statistically significantly lower in KO mice than in WT mice in all tissues examined. PhIP–DNA adducts in liver and kidney of WT mice were 9.9±1.1 and 22.5±6.9, respectively, whereas no PhIP–DNA adducts were detected in either organ of KO mice (limit of detection, 1.4–2.8×10⁹). PhIP–DNA adduct levels in mammary gland and colon of WT mice were 47.1±9.5 and 58.0±21.7, respectively, but accordingly only 3.8±0.7 and 5.4±0.9 in KO mice. The findings indicate that CYP1A2, responsible for IQ and PhIP N-hydroxylation, the first step in the metabolic action, significantly effects DNA adduct formation in vivo. However, the data raise the possibility that other cytochromes P450 as well as other pathways of activation potentially contribute to DNA adduct formation in specific organs, depending on the HCA substrate.

Section snippets

Acknowledgements

The authors thank Dr. Linda Byrd, Laboratory of Metabolism, NCI, for assistance with the mouse colony.

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Brief communicationEffect of CYP1A2 deficiency on heterocyclic amine DNA adduct levels in mice

Abstract

Section snippets

Acknowledgements

Mutation Research

Mutation Research

Cancer Letters

Cancer Letters

Food and Chemical Toxicology

Mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline by complementary DNA-expressed human liver P-450

Cancer Research

Mutagen activation by cDNA-expressed P1450, P3450, and P450a

Molecular Carcinogenesis

Cytochrome P-450 and acetyltransferase expression as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility

Progress in Clinical and Biological Research

Role of CYP1A2 in caffeine pharmacokinetics and metabolismstudies using mice deficient in CYP1A2

Pharmacogenetics

Human cytochrome P-450PA (P450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines

Proceedings of the National Academy of Sciences of the U.S.A.

Mutagenic activation of IQ, PhIP, and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo

Carcinogenesis

Contribution of CYP1A1 and CYP1A2 to the activation of heterocyclic amines in monkeys and human

Carcinogenesis

Possible mechanisms for PhIP-DNA adduct formation in the mammary gland of female Sprague–Dawley rats

Carcinogenesis

Metabolism of carcinogenic heterocyclic and aromatic amines by recombinant human cytochrome P450 enyzmes

Carcinogenesis

A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

Carcinogenesis

Metabolic polymorphisms and carcinogen-DNA adduct formation in human populations

Pharmacogenetics, 5, S108-S117

Metabolic activation pathway for the formation of DNA adducts of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat extrahepatic tissues

Carcinogenesis

Glucuronidation of N-hydroxy heterocyclic amines by human and rat liver microsomes

Carcinogenesis

Brief communication
Effect of CYP1A2 deficiency on heterocyclic amine DNA adduct levels in mice

Mutagen activation by cDNA-expressed P₁450, P₃450, and P450a

Human cytochrome P-450_PA (P450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines