The Bay Region Theory of Polycyclic Aromatic Hydrocarbon Carcinogenesis

Abstract

The hydrolysis rates, mutagenicities and tumorigenicities of a variety of diol epoxides and tetrahydroepoxides derived from polycyclic aromatic hydrocarbons (PAH) are examined. Bay-region diol epoxides and tetrahydroepoxides, as predicted by the "bay-region theory," are the most reactive and biologically active of those derivatives of a given PAH. A comparison of reactivity and mutagenicity data with a quantum chemical parameter that estimates chemical reactivity, ΔEdeloc/β, reveals a generally good correlation for the hydrolysis data, provided that diol epoxides within groups of similar conformational preference are compared. A similar result is found for the mutagenicity data when the analysis is confined to four- and five-ring PAH, with the significant exception of diol epoxides with the epoxide in a sterically hindered bay region, which are considerably more mutagenic than other diol epoxides with similar ΔEdeloc/β values. Three- and six-ring tetrahydro- and diol epoxides, however, exhibit consistently lower mutagenicities than their four- and five-ring counterparts with similar conformational preferences and ΔEdeloc/β values. Additional restrictions apply to tumorigenicity. To date, only bay-region diol epoxides that have preferred conformations with pseudodiequatorial hydroxyl groups have been found to be significantly tumorigenic, and those only when they have a relatively high calculated ΔEdeloc/β value or a highly hindered bay-region epoxide. Mutagenicity data for benz[a]- and benz[c]acridine diol epoxides and tetrahydroepoxides reveals a deactivating effect of nitrogen dependent upon its position relative to the epoxide. Benz[a]acridine bay region diol and tetrahydroepoxides have significantly reduced mutagenicities relative to their benz[a]anthracene counterparts, whereas the benz[c]-acridine non-bay tetrahydroepoxide on the angular benzo ring has significantly reduced mutagenicity.