Polycyclic Aromatic Hydrocarbons: The Nuclear Meabolizing System and Inability of Vitamen A Deficiency to Alter Metabolism, DNA Binding, And Subsequent DNA Repair

Abstract

Polycyclic aromatic hydrocarbons (PAR's) are ubiquitous environmental pollutants formed by incomplete combustion. Consequently, they are present in tobacco smo~e as well as in industrial effluents produced by the burning of fos~il fuels. Within this class of compounds,· many members are known carcinogens for animals and are, presumably, also carcinogenic for man. Since it is estimated that 80-90% of all human cancers have environmental factors as a component of their .etiology, the study of the mechanisms of PAH carcino'genesis is of paramount basic ·and clinical. importance. The carcinogenic PAH's require metabolic activation leading to the formation of "proxj_mate" and "ultimate" carcinogens. The latter activated electrophilic species bind to cellular macromolecules--DNA, RNA, anq protein--and.such . binding is postulated to be a critical event leading to neoplasia •. Repair of the lesion to macromolecules, e. g., DNA, may subsequently modify the results of~ such binding. ·In addition, a variety of these "post-initiation"· factors may ultimately determine whether or not such neoplastic transformation is clinically expressed. Metabolic activation had been believed to occur exclusively within the endoplasmic reticulum. Recently, however, the nucleus has been demonstrated to contain enzymes capable of activating PAH's. Nuclear activation is suspected t~ be of particular importance because of its proximity to the genetic apparatus of the cell and because of the.extreme lability of the putative ultimate metabolite of. the archetypal PAH-benzo[ a] pyrene (BP) . · The activation of BP .require.s. the concerted action of two enzymes--aryl hydrocarbon hydroxylase (AHH) and epoxide hydrase. Although the nuclear form of AHH had been studied prior to the present studies; nuc.le.ar. epoxide hydrase· has been poorly .characterized. In the studies herein reported, we have employed a "pincer" tactic in order to further characterize the metabolic activation of BP. Thus we· have, on·· the one hand, focused our attention on a specific nuclear enzyme activity--nuclear epoxide hydrase-.;..and have comp·ared and contrasted this activity with its microsomal counterpart. On the other hand, we have investigated the relationship between a known. ,modifier of BP tumorigenesis-- vitamin A def'iciency--and the metabolic activation of BP, its binding·to DNA, and the subsequent repc:tir of DNA.