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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026086-05
Application #
3167183
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-07-01
Project End
1987-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Maryland Balt CO Campus
Department
Type
Schools of Arts and Sciences
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21250