Initial chemical events caused by mutagenic heteroaromatic amines.

Abstract

Initial chemical events caused by mutagenic heteroaromatic amines are discussed. 2-Amino-6-methyldipyrido [1, 2-a : 3', 2'-d] imidazole (Glu-P-1) and 3-amino-1-methyl-5H-pyrido [4, 3-b] indole (Trp-P-2) are potent mutagens isolated from pyrolysates of glutamic acid and tryptophan, respectively. These carcinogens are N-hydroxylated with microsomes to give the corresponding hydroxylamines. These hydroxylamines are O-acylated with cytosol to give the corresponding N-acyloxy derivatives, which react with DNA. The structures of the modified nucleic acid bases with Glu-P-1 and Trp-P-2 were determined to be 2-(guanin-8-yl) amino-6-methyldipyrido [1, 2-a : 3', 2'-d] imidazole (Gua-Glu-P-1) and 3-(guanin-8-yl) amino-1-methyl-5H-pyrido [4, 3-b] indole (Gua-Trp-P-2), respectively. Syntheses of these heteroaromatic amines, these modified nucleic acid bases and metabolically activated hydroxylamines are described. Reactions of model compounds of the ultimate forms of these heteroaromatic amines with nucleic acids were investigated. Thus, the pathway of the chemical modification of DNA with Glu-P-1 and with Trp-P-2 were established chemically. In addition, the same chemical modification of DNA with Glu-P-1 and with Trp-P-2 were observed in vivo (rats). In the pathway, intercalation of these heteroaromatic amines is an important factor which makes the covalent reaction facile and determines the mutagenic activity. Intercalative ability of Glu-P's were established by physical methods. The chemical modification of DNA is quite specific to the 8-position of guanine moiety, and the guanine moieties in G-C rich regions are preferentially modified. The established pathway of chemical modification of DNA with Glu-P-1 and with Trp-P-2 provides a fundamental standpoint in the study on chemical carcinogenesis caused by these heteroaromatic amines.