Nucleic acid base and carcinogen metabolite specificities during intercalative interactions between DNA and 4-nitroquinoline 1-oxide.

Abstract

Intercalation of the carcinogen 4-nitroquinoline 1-oxide (4-NQO) or its metabolic intermediate forms, probably precedes the covalent bond formation of the ultimate carcinogenic form with DNA. A 'complete' empirical-potential energy description of the base-sequence and metabolite specificities of the 4-NQO intercalation process is presented in this work. The important force and structural interaction components are depicted via decomposed energy functions. Energy-minimized intercalated complexes are presented and indicate several interesting characteristics. It is clear that the various intercalated quinoline-metabolites do not generally enter into 'strictly' parallel-planar stacked orientations (unlike the structurally rigid ethidium-intercalated complexes). Intercalation is energetically permitted for six of seven quinoline-metabolites (QMS) studied, although, intercalation into to Pyr(3'-5')Pur sequences is preferred over Pur(3'-5'1Pyr sequences. The three quinoline-metabolites that are more energetically favoured to undergo intercalation than the parent form are also known to enter into the greatest amount of covalent interactions with DNA and its constituents. Thus the present work further suggests the existence of a two-step binding mechanism: intercalation followed by covalent reaction.