[71] Chemical carcinogenesis: Benzopyrene system

It has been realized that the metabolic activation of chemical carcinogens may lead to free-radical intermediates, which may be related to the action of chemical carcinogens. There is considerable interest in evaluating the importance of such radical intermediates on the toxic, mutagenic, tumor-initiating, and tumor-promoting capacities of the relevant carcinogens. The metabolic activation of benzo[a]pyrene (BP), an important environmental carcinogen, has been extensively investigated. Several major BP metabolites, 6-hydroxy-BP, BP-1,6-dione, BP-3,6-dione, and BP-6,12-dione give rise to free-radical intermediates and reactive reduced oxygen species as the result of autoxidative processes and redox cycles. These metabolites induce DNA strand scission in vitro and are cytotoxic to mammalian cells in culture. The metabolic conversion of BP to reactive electrophiles as well as intermediates that generate reactive oxygen species may account for its ability to serve as a complete carcinogen––that is, having both initiating and promoting activities. This chapter reviews the preparation, purification, and chemical properties of 6-hydroxy-BP and the three isomeric BP diones.