title: A structure-based investigation on the binding interaction of hydroxylated polycyclic aromatic hydrocarbons with DNA.
abstract: Binding of polycyclic aromatic hydrocarbons (PAHs) with DNA is one of the key steps in their mutagenic process. In this work, a previously established electrochemical displacement method was utilized to measure the binding constants (K(b)) of 26 hydroxylated PAHs (OH-PAHs) with DNA. Eighteen OH-PAHs induced more than 50% signal reduction in the displacement measurement with calf thymus DNA, and K(b) calculated from the EC(50) value is between 8.3 x 10(4) and 3.0 x 10(5)M(-1). Other eight OH-PAHs induced less than 50% signal reduction. For the latter compounds, EC(50) values were obtained by fitting the displacement curve with a bi-exponential decay function and extrapolating it to 50% signal. K(b) was then calculated, and was found to be in the range of 4.5 x 10(4) and 7.6 x 10(4)M(-1). Measurements with polydG.polydC (pdGC) and polydA.polydT (pdAT) demonstrate that the OH-PAHs have no obvious selectivity toward DNA base pairs. In atomic force microscopy, a clear morphological change of calf thymus DNA from linear type to condensation form was observed after binding with 9-hydroxyfluorene. The change is similar to the one observed with the DNA-intercalating electrochemical indicator, suggesting that 9-hydroxyfluorene binds with DNA also by intercalation. An examination of the relationship between the molecular structure characteristics of the 26 OH-PAHs and their DNA-binding affinity revealed that the most positive net atomic charge on a hydrogen atom (q(+)(H)) correlated significantly with K(b) at 0.05 level, with sig. (2-tailed) of 0.015. The correlation suggests that hydrogen bonding may play an important role in DNA/OH-PAH binding interaction. It was further revealed that Connolly accessible area (CAA), Connolly molecular area (CMA), and Connolly solvent-excluded volume (CSEV) of the nine hydroxybenzo[a]pyrenes correlated significantly with K(b) at 0.01 or 0.05 level, with sig. (2-tailed) 0.019, 0.012 and 0.009, implying that steric effect might be an important factor in the binding of differently substituted OH-PAH with DNA.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Li-Rong
authors: LR
authors: Wang
authors: Ying
authors: Y
authors: Wang
authors: Jing-Wen
authors: JW
authors: Chen
authors: Liang-Hong
authors: LH
authors: Guo
mesh_terms: D000818:Animals; D020029:Base Pairing; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D006860:Hydrogen Bonding; D018625:Microscopy, Atomic Force; D009153:Mutagens / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; D004247:DNA; C427203:calf thymus DNA