This is a new application based upon the hypothesis that diol epoxides may not be the only class of oxidized PAH product which is of importance to an understanding of carcinogenesis. Specifically, it is proposed that polycyclics which possess more than one bay or fjord region may undergo multiple oxidation reactions in cells, so as to form the bis dihydrodiol, dihydrodiol monoepoxide, or phenolic dihydrodiol epoxide. Based upon a review of the current literature it is proposed that these higher order oxidation products may, in certain instances, be a major origin of DNA damage, leading to toxicity, mutation and, in certain instances, carcinogenesis.
The specific aims of the proposal are to focus on specific adducts of that kind, namely the corresponding dibenz(a,j)anthracene, the dibenz(a,h)anthracene, benzo(c)chrysene, benzo(s)picene, dibenzo(b,def)chrysene and naphtho(1,2,3,4- rst)pentaphene. These were chosen because they are known carcinogens, which if Dr. Harvey's model is correct, would be subject to the multiple oxidations proposed in the model. Dr. Harvey proposes to develop new synthetic procedures to obtain the racemic parent compounds, then extend the work so as to obtain stereochemically pure isomers of the bis-dihydrodiols. The resulting compounds will then be tested for mutagenicity by Dr. Harvey, and will be supplied to collaborators and other researchers for biological and structural studies. The synthetic compounds will be furnished to Dr. Penning to determine whether the bis-dihydrodiols are substrates for the dehydrogenase enzyme and whether the quinones formed can participate in a redox cycle with O2 to generate reactive oxygen species. It is also planned to study in collaboration with Dr. Geacintov the structures of DNA adducts formed by bis-dihydrodiol monoepoxides and bis-dihydrodiol diepoxides. The bis-dihydrodiol diepoxides are potentially capable of cross-linking nucleic acids with important biological consequences.
