Dihydrodiol epoxides

Figure 2. 7-Methylbenz[a]anthracene and benzo[a]pyrene indicating those regions defined as bay regions and the structures of the corresponding bay region dihydrodiol epoxides.

In the newborn mouse system (Table II), the (+) anti dihydrodiol epoxide is clearly more effective than benzo[ajpyrene but this is not the case in initiation-promotion studies or in complete carcinogenesis studies on mouse skin. Nevertheless, there is always... 

Figure 4. The bay region dihydrodiol epoxide route of metabolism of benzo[a]pyrene.

Structures of 5-MeC bay region dihydrodiol epoxides and their precursor dihydrodiols. 

The rates of hydrolysis and binding to DNA of anti-DE-I, syn-DE-I, anti-DE-II, syn-DE-II, and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (anti-chrysene-DE) were studied in order to relate the chemical reactivity of these dihydrodiol epoxides to their biological activities. The half-lives of the dihydrodiol epoxides in cacodylate buffer at pH 7.0 and 37°C are summarized in Table III and their relative extents of binding to DNA in Table IV. It is clear that the rates of hydrolysis of the dihydrodiol epoxides do not correlate with their DNA binding properties. 

Table III. Half-Lives of Dihydrodiol Epoxides of 5-MeC and Chrysene at pH 7.0 and 37 °C in the Absence and Presence of Native and Denatured Calf Thymus DNA...

Plot of the ratios of the half-lives of dihydrodiol epoxides in the presence of denatured DNA to those in the presence of native DNA vs. extents of DNA binding in vitro. 

Reactive Metabolites of PAHs. A wide variety of products have been identified as metabolites of PAHs. These include phenols, quinones, trans-dihydrodiols, epoxides and a variety of conjugates of these compounds. Simple epoxides, especially those of the K-region, were initially favored as being the active metabolites responsible for the covalent binding of PAH to DNA. Little direct experimental support exists for this idea (62.63,64) except in microsomal incubations using preparation in which oxidations at the K-region are favored (65,66). Evidence has been presented that a 9-hydroxyB[a]P 4,5-oxide may account for some of the adducts observed in vivo (67.68) although these products have never been fully characterized. 

Studies on the comparative abilities (13) of B[a]P metabolites to bind to DNA in microsomal systems showed that the 7,8-dihydrodiol was the most efficient. This led to the proposal (69) that dihydrodiol epoxides were the ultimate carcinogenic metabolites. Chemical synthesis of all possible isomers (70.71) has allowed complete structural identification of the adducts (72-74). 

Bowden, G.T., Hsu, I.C., and Harris, C.C. (1979). The effect of caffeine on cytotoxicity, mutagenesis and sister chromatid exchanges in Chinese hamster cells treated with dihydrodiol epoxide derivatives of benzo(a)pyrene. Mutation Res. 63 361-370. 

In contrast, the pathway best known to yield adduct-forming metabolites (the ultimate carcinogens) is the formation of dihydrodiol epoxides, usually referred to as diol epoxides . This pathway involves three steps a) formation of an M-region epoxide, b) its hydration to the M-region dihydrodiol, and c) epoxidation of the latter at the vicinal C=C bond bordering the bay or fjord region. 

The formation and reactivity of dihydrodiol epoxides is now illustrated for benzo[a]pyrene (BaP, 10.34, Fig. 10.13), one of the most extensively investigated PAHs and a highly active carcinogen. However, far from being exclusive to BaP, this toxification pathway is known to occur for a number of PAHs containing a bay or fjord region. 

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