Reactivity and tumorigenicity of bay-region diol epoxides derived from polycyclic aromatic hydrocarbons.
During the past decade substantial progress has been made in elucidating factors that determine the tumorigenic activity of bay-region diol epoxides, major ultimate carcinogenic metabolites derived from polycyclic aromatic hydrocarbons. Neither high nor low chemical reactivity of the diol epoxides (as measured by rates of uncatalyzed solvolysis) is required for high tumorigenic response. In contrast, aspects of molecular structure such as conformation and absolute configuration strongly influence tumorigenic activity. The role of conformation is illustrated by the observation that those diol epoxides whose hydroxyl groups are pseudoaxial are weak or inactive as tumorigens. Absolute configuration is an important determinant of biological activity of bay-region diol epoxides: in all cases studied to date, the predominantly formed (R,S)-diol-(S,R)-epoxides are generally the most tumorigenic of the four metabolically possible configurational isomers. In the course of investigating the effects of structural factors on tumorigenic activity, we identified the (4R,3S)-diol-(2S,1R)-epoxide of benzo(c)phenanthrene as the most potent tumorigen (in initiation-promotion experiments on mouse skin) of the diol epoxides studied to date. Studies of all four configurationally isomeric diol epoxides derived from benzo(c)phenanthrene led to the striking observation that these diol epoxides exhibit an exceptionally high efficiency of covalent binding, relative to hydrolysis, when allowed to react with calf thymus DNA in aqueous solution. Thus, these diol epoxides should provide an excellent tool for the detailed study of such binding. When the four isomeric benzo(c)phenanthrene diol epoxides are compared, there appears to be no simple correlation between tumorigenic response and either the extent of binding to DNA or the major types of deoxyribonucleoside adducts formed. Deoxyribonucleoside adducts of benzo(c)phenanthrene diol epoxide have also been identified from the DNA of cultured rodent embryo cells after treatment of the cells with tritium-labeled benzo(c)phenanthrene. The distribution of adducts is consistent with predominant metabolic formation of the (4R,3S)-diol-(2S,1R)-epoxide; deoxyadenosine is the major site in the cellular DNA attacked by this epoxide, just as it is in DNA in solution. Further experiments are in progress which we hope will identify more subtle aspects of the DNA binding of benzo(c)phenanthrene diol epoxides that may be uniquely correlated with their tumorigenic activity.
D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D003839:Deoxyadenosines; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010616:Phenanthrenes / Q000378:metabolism; D011083:Polycyclic Compounds; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002273:Carcinogens; D003839:Deoxyadenosines; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D010616:Phenanthrenes; D011083:Polycyclic Compounds; D004247:DNA