Journal Article

Syntheses of DNA adducts of two heterocyclic amines, 2-amino-3-methyl-9<i>H</i>-pyrido[2,3-<i>b</i>]indole (MeAαC) and 2-amino-9<i>H</i>-pyrido[2,3-<i>b</i>]indole (AαC) and identification of DNA adducts in organs from rats dosed with MeAαC

Hanne Frederiksen, Henrik Frandsen and Wolfgang Pfau

in Carcinogenesis

Volume 25, issue 8, pages 1525-1533
Published in print August 2004 | ISSN: 0143-3334
Published online August 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh156
Syntheses of DNA adducts of two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) and 2-amino-9H-pyrido[2,3-b]indole (AαC) and identification of DNA adducts in organs from rats dosed with MeAαC

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2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (AαC) are mutagenic and carcinogenic heterocyclic amines formed during ordinary cooking. MeAαC and AαC are activated to mutagenic metabolites by cytochrome P450-mediated N-oxidation to the corresponding N2-OH derivatives. The proximate mutagenic N2-OH derivatives of MeAαC and AαC did not react with deoxynucleosides or DNA. However, upon acetylation with acetic anhydride both reacted with 2′-deoxyguannosine and 3′-phospho-2′-deoxyguanosine, resulting in one adduct each, but not with other nucleosides or nucleotides. The adducts were identified as N2-(2′-deoxyguanosin-8-yl)-MeAαC, N2-(2′-deoxyguanosin-8-yl)-AαC, N2-(3′-phospho-2′-deoxyguanosin-8-yl)-MeAαC and N2-(3′-phospho-2′-deoxyguanosin-8-yl)-AαC by comparison with adducts of known structure obtained by reaction of the parent amines with acetylated guanine N3-oxide. N2-OH-MeAαC and N2-OH-AαC reacted with calf thymus DNA after addition of acetic anhydride. 32P-postlabelling analysis of modified DNA showed one major adduct co-migrating with N2-(3′,5′-diphospho-2′-deoxyguanosin-8-yl)-MeAαC and N2-(3′,5′-diphospho-2′-deoxyguanosin-8-yl)-AαC, respectively. Some minor adducts presumed to be undigested oligomers were also detected. 32P-postlabelling analysis of DNA from several organs of rats dosed orally with MeAαC showed that in vivo N2-(2′-deoxyguanosin-8-yl)-MeAαC also was the major adduct formed. Relative adduct level in DNA isolated from the liver of the rats was about 50.40 adducts/109 nt. The adduct levels were ∼4-fold lower in the colon and the heart and ∼12-fold lower in the kidney of the rats.

Keywords: AαC, 2-amino-9H-pyrido[2,3-b]indole; dG-AαC, N2-(2′-deoxyguanosin-8-yl)-AαC; dG-MeAαC, N2-(2′-deoxyguanosin-8-yl)-MeAαC; 4,8-DiMeIQx, 2-amino-3,4,8-trimethyl-imidazo[4,5-f]quinoxaline; G-AαC, N2-(guanin-8-yl)-AαC; G-MeAαC, N2-(guanin-8-yl)-MeAαC; IQ, 2-amino-3-methylimidazo[4,5-f]quinoxaline; MeAαC, 2-amino-3-methyl-9H-pyrido[2,3-b]indole; MeIQx, 2-amino-4,8-dimethylimidazo[4,5-f]quinoxaline; P-dG-AαC, N2-(3′-phospho-2′-deoxyguanosin-8-yl)-AαC; P-dG-MeAαC, N2-(3′-phospho-2′-deoxyguanosin-8-yl)-MeAαC; PhIP, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine; RAL, relative adduct level

Journal Article.  5654 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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