PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH

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This proposal concerns the metabolism, biological activity and DNA adduct formation of a series of PAH which may be activated via epoxidation of a cyclopenta ring fused to the molecular periphery: cyclopenta(cd)pyrene, I benz(j)aceanthrylene, II; benz(l)aceanthrylene, III; naphtho (2,1,8-hij)acephenanthrylene, IV; and dibenzo(b, mno)acephenanthrylene, V. The long-term goals of this study are to gain insight into the effects of molecular geometry and peripheral functionalization (e.g. vicinal hydroxy groups of diolepoxides) on mutagenic and carcinogenic activity. Such information will ultimately be important in the rational selection of DNA lesions to serve as models is the elucidation of mechanisms linking DNA adducts to genetic effects. Of the PAH proposed for study, preliminary results on the metabolism and biological activity of I - III demonstrate that these compounds transform C3H10T1/2 cells, form DNA adducts and that the most potent activity results from II which can be activated either by a cyclopenta epoxide or a bay region diolepoxide. Compound I should be activated by cyclopenta ring epoxidation and III must be activated by multiple pathways. Short terms goals will be (1) synthesis of IV, V and determination of mutagenicity and cell transforming activity; (2) identification of ultimate active metabolities of I - III and/or IV, V (contingent on cell transforming activity); (3) synthesis of standards for identification of DNA adducts of I - III and/or IV, V,; (4) identification and quantitation of DNA adducts of C3H1OT1/2 cells treated with the tographic properties of adducts and suitably prepared standards by 32-p-postlabeling techniques or by HPLC, utilizing 3H-labeled PAH for treatment of C3H10T1/2 cells. Conclusions should be possible regarding the importance of the bay region diolepoxide metabolites in cell transformation and their activity relative to cyclopenta epoxides, as well as the generality of the regioselectivity of activated PAH metabolites for addition to the exocyclic amino group of guanosine and the relevance of this lesion to the transformation of C3H10T1/2 cells.