Carcinogenesis Advance Access originally published online on April 1, 2004
Carcinogenesis 2004 25(8):1525-1533; doi:10.1093/carcin/bgh156
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Carcinogenesis vol.25 no.8 © Oxford University Press 2004; all rights reserved.
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Syntheses of DNA adducts of two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA
C) and 2-amino-9H-pyrido[2,3-b]indole (AC) and identification of DNA adducts in organs from rats dosed with MeAC
Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration, Mørkhøj Bygade 19, DK 2860 Søborg, Denmark and 1 Institute of Clinical and Experimental Toxicology, Hamburg University Medical School, Vogt-Kolln Strasse 30, D22527 Hamburg, Germany
2 To whom correspondence should be addressed Email: haf{at}fdir.dk
2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA
C) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (AC) are mutagenic and carcinogenic heterocyclic amines formed during ordinary cooking. MeAC and AC are activated to mutagenic metabolites by cytochrome P450-mediated N-oxidation to the corresponding N2-OH derivatives. The proximate mutagenic N2-OH derivatives of MeAC and AC 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)-MeAC, N2-(2'-deoxyguanosin-8-yl)-AC, N2-(3'-phospho-2'-deoxyguanosin-8-yl)-MeAC and N2-(3'-phospho-2'-deoxyguanosin-8-yl)-AC by comparison with adducts of known structure obtained by reaction of the parent amines with acetylated guanine N3-oxide. N2-OH-MeAC and N2-OH-AC 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)-MeAC and N2-(3',5'-diphospho-2'-deoxyguanosin-8-yl)-AC, 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 MeAC showed that in vivo N2-(2'-deoxyguanosin-8-yl)-MeAC 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.
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