Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA

摘要

The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites formed enzymatically to DNA is a crucial step in PAH carcinogenesis in vivo We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding The dissociation constants ranged from 002 to 12 34 mu M Of the metabolites tested 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA while 2-naphthol was the weakest DNA intercalator The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites and DNA bases or backbones The binding of the metabolites to DNA showed some sequence selectivity The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene benzo[a]pyrene-4 5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7 t-8-dihydrodiol-t-9 10-epoxide (BPDE) differed It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites the present study improved our understanding of the formation of PAH metabolite-DNA adducts (C) 2010 Elsevier B V All rights reserved