Epoxide-dihydrodiol pathway hydrocarbons

The Epoxide-Dihydrodiol Pathway of Bicyclic and Tricyclic Aromatic Hydrocarbons... 

The polycyclic aromatic hydrocarbon carcinogens, which are very ubiquitous, are metabolized by the microsomal mixed-function oxidase system of target tissues to a variety of metabolites such as phenols, quinones, epoxides, dihydrodiols and dihydrodiol-epoxides ( ). The mqjor pathway of activation of benzo(a)pyrene (BP) leads to the formation of dihydrodiol-epoxide of BP which interacts predominantly with the 2-amino of guanine of DNA. The dihydrodiol-epoxide of BP appears to be the major ultimate electrophilic, mutagenic, and carcinogenic metabolite of BP ( ). Nevertheless, other metabolites such as certain phenols, epoxides and quinones may contribute to the overall carcinogenic activity of BP. In addition, a free radical mechanism may also be partly involved in its carcinogenic activity. 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

In the pH range of 5 - 10, H20-catalyzed hydrolysis is the predominant mechanism (see Fig. 10.11, Pathway b), resulting in the formation of the (8R,9R)-dihydrodiol (10.133, Fig. 10.30). Thus, aflatoxin B1 exo-8,9-epoxide is possibly the most reactive oxirane of biological relevance. Such an extreme reactivity is mostly due to the electronic influence of 0(7), as also influenced by stereolectronic factors, i.e., the difference between the exo- and endo-epoxides. The structural and mechanistic analogies with the dihydro-diol epoxides of polycyclic aromatic hydrocarbons (Sect. 10.4.4) are worth noting. 

As well as detoxication via reaction with GSH, the reactive 3,4-epoxide can be removed by hydration to form the dihydrodiol, a reaction that is catalyzed by epoxide hydrolase (also known as epoxide hydratase). This enzyme is induced by pretreatment of animals with the polycyclic hydrocarbon 3-methylcholanthrene, as can be seen from the increased excretion of 4-bromophenyldihydrodiol (Table 7.5). This induction of a detoxication pathway offers a partial explanation for the decreased hepatotoxicity of bromobenzene observed in such animals. A further explanation, also apparent from the urinary metabolites, is the induction of the form of cytochrome P-450 that catalyzes the formation of the 2,3-epoxide. This potentially reactive metabolite readily rearranges to 2-bromophenol, and hence there is increased excretion of 2-bromophenol in these pretreated animals (Table 7.5). 

Biological activation of polycyclic-hydrocarbon carcinogens proceeds through dihydrodiols and diol epoxides and such pathways are clearly possible for aza-aromatic compounds. To assist in investigating the existence of such routes, a range of dihydrodiols and diol epoxides of benz[c]acridine and benz[a]acridine (R.E. Lehr and S. Kumar, J. org. Chem., 1981, 367 ... 

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