title: Computational study of the reactivity of bisphenol A-3,4-quinone with deoxyadenosine and glutathione.
abstract: Bisphenol A is a monomer used in the production of polycarbonate plastics, epoxy resins, and flame retardants. It is an endocrine disruptor with a variety of other effects, including genotoxicity. Oxidative metabolism of bisphenol A yields electophilic bisphenol A-3,4-quinone (BPAQ), which may cause genotoxicity. To determine the genotoxic potential of bisphenol A, the mechanism of the reaction between the BPAQ and deoxyadenosine (dA) was studied in detail. The most probable reaction pathway was determined using quantum chemical methods. Our results demonstrate that the rate limiting step is Michael addition between BPAQ and dA, the main product being the unstable N7-modified adduct that rapidly undergoes depurination. In addition, our calculations provide strong evidence for protonation of the adducts prior to depurination, which indicates pH dependence of the reaction. The calculated activation barrier for Michael addition is 28.7 kcal/mol, indicating that the reaction with dA is very slow. Comparison with the activation energy of 23.1 kcal/mol for the corresponding deoxyguanosine reaction indicates that most of the DNA damage by BPAQ will occur at the guanine site. The detoxification reactions with glutathione compete with reactions between BPAQ and DNA. The calculated free energy of activation for the reaction with glutathione is significantly lower than that for the corresponding reaction with dA. This indicates that BPAQ will preferably react with glutathione and will only react with DNA when the level of glutathione in the cell is low.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Katra
authors.initials: K
authors.lastname: Kolšek
authors.forename: Marija
authors.initials: M
authors.lastname: Sollner Dolenc
authors.forename: Janez
authors.initials: J
authors.lastname: Mavri
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry*; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry*; D011789:Quantum Theory; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D016227:Benzoquinones; D018736:DNA Adducts; D003839:Deoxyadenosines; D005978:Glutathione; D010636:Phenols; C487806:bisphenol A 3,4-quinone; D000098826:Bisphenol A Compounds; C006780:bisphenol A