Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

Abstract

Tumorigenic activities of the (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of benzo [a]pyrene [(+)-B[a]P diol epoxide-21 and 6-fluorobenzo- [a]pyrene (6-FB[a]P diol epoxide-2) were evaluated in newborn CD-1 mice. A total dose of 14 nmol of either diol epoxide was administered to preweanling mice, and tumorigenic activity was determined when the mice were 32 to 36 weeks old. At the termination of the study, 13% of solvent-treated control mice had developed lung tumors with an average of 0.19 tumor per mouse. No other tumors were observed in control animals.(+)-B[a]P diol epoxide-2 induced pulmonary tumors in 60% of the mice with an average of 1.9 tumors per mouse, and 14% of the male mice developed hepatic tumors with an average of0.18 tumor per mouse. In contrast, 6-FB[a]P diol epoxide-2 had no significant tumorigenic activity at the 14-nmol dose. Although both bay-region diol epoxides have the same absolute configuration, (7R,8S,9S,1OR), the hydroxyl groups of (+)-B[a]P diol epoxide-2 prefer the pseudoequatorial conformation whereas the hydroxyl groups of 6-FB[a]P diol epoxide-2 prefer the pseudoaxial conformation. The tumorigenicity results reported here are the first direct demonstration that conformation of the hydroxyl groups in a bay-region diol epoxide, in addition to the documented effect of absolute configuration, is an important determinant in the tumorigenic activity of these ultimate carcinogens.The bay-region diol epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene exist as a pair of diastereomers in which the 7-hydroxyl group is either cis (diol epoxide-1) or trans (diol epoxide-2) to the 9,10-epoxide oxygen. In the absence of specific structural features, the hydroxyl groups of benzo-ring dihydrodiols prefer the pseudoequatorial conformation (1). Although this conformational preference is maintained for the diol epoxide-2 diastereomers, the diol epoxide-1 diastereomers have a slight preference for the conformation in which the hydroxyl groups are pseudoaxial (2)(3)(4)(5). Tumor studies with bay-region diol epoxides derived from benzo[a]pyrene (B[a]P) (6, 7), chrysene (8, 9), benz[a]anthracene (10,11), and benz[c]acridine (12,13) have shown that the diol epoxide-2 diastereomers have high tumorigenic activity relative to the diol epoxide-1 diastereomers, which in some cases are inactive. Both diastereomers of the benzo[e]pyrene bay-region 9,10-diol-11,12-epoxides, which have their hydroxyl groups essentially locked in the pseudoaxial conformation due to steric crowding in the bay region (14), have little or no tumorigenic activity (15). These observations have implicated the potential importance of conformational factors in the expression of tumorigenic activity of bay-region diol epoxides.

Quantification of benzo[a]pyrene diol epoxide DNA‐adducts by stable isotope dilution liquid chromatography/tandem mass spectrometry

“…All four B[ a ]PDE diastereomers are mutagenic in bacterial and mammalian cell assays 33, 34. However, (+)‐ anti ‐B[ a ]PDE is the most tumorigenic, causing pulmonary adenomas in mice 35–37. In order to determine the relative importance of the CYP‐, AKR‐ and radical‐cation‐mediated pathways of B[ a ]P metabolism (Scheme ), we required a method to specifically quantify the (±)‐ anti ‐B[ a ]PDE‐derived dGuo‐ and dAdo‐adducts that are formed in DNA (Scheme ).…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…The reason may be that the hydroxyl groups in the sterically hindered fjord-region DEs remain in a pseudodiequatorial position, which is not the case in the weakly active syn-diastereomers of the bay-region DEs (Figure 10). The importance of the spatial orientation of the hydroxyl groups for the biological activity has been shown experimentally (Chang et al 1987). The crowdedness in the fjordregion renders these compounds nonplanar in contrast to the planar bay-region DEs.…”

Biochemistry of the Elemental Halogens and Inorganic Halides

“…A more subtle effect of fluorine substitution on carcinogenicity of PAHs has been described recently (Chang et at., 1987). The diol epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzo [a] pyrene have the 7hydroxyl group either cis or trans to the 9,10-epoxide oxygen.…”

“…Effect of fluorine substitution on the conformation of diol epoxides. Adapted, with permission, from Chang et al, 1987. Metabolism of Halogenated Compounds-Biodehalogenation 279 absence of metabolites in liver and fat indicates that, once formed, metabolites are quickly cleared (Neal et al, 1984). There are quantitative differences in metabolism of TCDD in various mammalian species.…”