The relationship between inflammation and the development of cancer hasn't been mechanistically elucidated. It has been shown that polymorphonuclear leukocytes can metabolize the proximate carcinogen benzo[a]pyrene-7,8-diol (BP-7,8-diol) to its ultimate tumor- initiating form, BP-7,8-diol-9,10-epoxide. A second reaction pathway, that of the formation of a dioxetane metabolite, can generate not only electrophilic species, but also produce genotoxic reactive oxygen species as well as a chemiluminescence (CL) response. This response is thought to be produced by a dioxetane ring-opening to a dialdehyde intermediate, and can be increased and prolonged by the addition of taurine to the reaction mixture. A Schiff base formation of the dialdehyde and taurine has been proposed. The objectives of this proposal are to determine the necessary elements for this Schiff base formation and what damage this formation can cause in DNA. This will be accomplished by determining the bound products of BP-7,8- diol and taurine as well as the structural requirements for both the dialdehyde and amine donor components of the Schiff base. The groups of enzymes which can catalyze this reaction will also be investigated. The DNA damage produced by this reaction pathway will be investigated by 32P-postlabeling analysis using a procedure which will simultaneously determine oxidized DNA bases and hydrocarbon- bound DNA bases.
