Carcinogenesis Advance Access published online on April 1, 2004
Carcinogenesis, doi:10.1093/carcin/bgh156
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration, Mørkhøj Bygade 19, DK 2860 Søborg, Denmark
* Corresponding author. E-mail: haf{at}fdir.dk.
Received 10 December 2003
; revised 19 March 2004
; accepted 22 March 2004
2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA The proximate mutagenic N2-OH-derivates of MeA
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
2 Institute of Clinical and Experimental Toxicology, Hamburg University Medical School, Vogt-Kolln Strasse 30, D22527 Hamburg, Germany
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.C 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 nucleotides. The adduct levels were about four fold lower in the colon and the heart and about twelve fold lower in the kidney of the rats.
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