MECHANISMS OF CHEMICAL CARCINOGENESIS: POLYCYCLIC AROMATIC HYDROCARBON METABOLISM AND DNA ADDUCT FORMATION
Abstract
There is a direct correlation between the tumor initiating activity of polycyclic aromatic hydrocarbons (PAH) and their covalent binding to target tissue DNA. Benzo(e)pyrene (B(e)P), acts as a cocarcinogen with benzo(a)pyrene (B(a)P) and as an anti -carcinogen with 7,12-dimethylbenz(a)anthracene (DMBA). Studies of the effects of B(e)P on the binding of B(a)P and DMBA to DNA of mouse epidermis demonstrated that the effects of B(e)P on tumor initiation in mice by B(a)P and DMBA correlate with the effects on the amount of B(a)P or DMBA bound to epidermal DNA. Studies of the effects of B(e)P on the metabolic activation of B(a)P or DMBA in hamster embryo cell cultures have shown that the dose of initiator, the ratio of B(e)P to initiator, and the lengths of time of exposure are all critical factors in determining the stereoselective changes induced by B(e)P on metabolic activation and DNA adduct formation by DMBA and B(a)P. Benz(a)anthracene (BA), a hydrocarbon that induces monooxygenases, inhibited the metabolic activation of B(a)P when coadministered with B(a)P. In contrast, induction of the monooxygenases by pre-exposure to B(a)P in hamster embryo cell cultures increased the formation of DNA adducts by the ultimate carcinogenic metabolite $(+)$- anti -B(a)P-7,8-diol-9,10-epoxide (epoxide and benzylic hydroxl are trans). Studies of PAH metabolism in fish cell cultures demonstrated that the ability of a species to conjugate carcinogen metabolites affects the amount of PAH bound to DNA. A nitrocellulose filter assay and immunoaffinity columns utilizing rabbit antisera directed against DNA modified by anti -Benzo(c)phenanthrene-diol epoxide were developed to isolate hydrocarbon-modified DNA sequences. A number of factors that influence chemical carcinogenesis by PAH including cocarcinogens, induction of specific monooxygenases, and species dependent differences in the formation of water-soluble PAH conjugates, all modify PAH-DNA interactions. The measurement of PAH-DNA interactions is of value in predicting the effect of various modifying factors on the carcinogenicity of PAH.
Degree
Ph.D.
Subject Area
Biochemistry
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