The goals of this research are to study the nucleic acid and micelle-catalyzed hydrolysis reactions of epoxide metabolites derived from both carcinogenic and non-carcinogenic aromatic hydrocarbons. Initially, the hydrolysis reactions of the diastereomeric syn and anti 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene metabolites catalyzed by various synthetic single- and double-stranded polynucleotides will be studied. Non-covalent, pre-equilibrium binding constants for reaction of these diol epoxides with each polynucleotide will be measured, along with maximal rates for nucleic acid-bound epoxide as a function of pH. In view of the finding that the (+) enantiomer of the anti diol epoxide metabolite of benzo[a]pyrene is highly tumorigenic in test animals, whereas the (-) enantiomer is essentially nontumorigenic, and effort will be made to determine if there are any significant differences in the kinetic parameters or covalent binding products in the reactions of the (+) and (-) enantiomers of this diol epoxide metabolite with synthetic polynucleotides. Effects of epoxide structure, and also of primary and secondary nucleic acid on both non-covalent binding constants and maximal rates will be determined. Those epoxides that will be studied are the bay region diol epoxides and tetrahydroepoxides of benzo[a]pyrene, chrysene, phenanthrene, naphthalene, and perhaps benzo[a]anthracene. The nucleic acids to be used in our studies are polyguanilic acid, polyadenylic acid, polycytidylic acid, polyadenylic acid-polyuridylic acid, and DNA. Salt effects on nucleic acid-catalyzed epoxide hydrolyses will also be measured. In order to more fully understand the driving force behind the nucleic acid-catalyzed hydrolysis of diol epoxides, we also plan to generate rate profiles of diol epoxide hydrolyses in solutions containing anionic, cationic, and neutral micelles as a function of pH and salt concentration.
| Islam, N B; Whalen, D L; Yagi, H et al. (1988) Kinetic studies of the reactions of benzo[a]pyrene-7,8-diol 9,10-epoxides in aqueous solutions of human serum albumin and nonionic micelles. Chem Res Toxicol 1:398-402 |
