Polycyclic aromatic hydrocarbons reactive metabolites

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

Initially, particular attention was focused on the epoxides of the so-called K region. As in the case of benzo [a] pyrene and certain other polycyclic aromatic hydrocarbons, these were more carcinogenic than the parent compound. The K region had attracted particular interest, as it is electronically the most reactive portion of the polycyclic aromatic hydrocarbon molecule. However, with other carcinogenic polycyclic aromatic hydrocarbons, this was not found to be the case. It now seems that the ultimate carcinogen is an epoxide of a dihydrodiol metabolite, where the epoxide is adjacent to the so-called bay region (Fig. 7.2). 

Formation of a dihydrodiol by hydration of epoxide groups can be an important detoxication process in that the product is often much less reactive to potential receptors than is the epoxide. However, this is not invariably the case because some dihydrodiols may undergo further epoxidation to form even more reactive metabolites. As shown in Figure 7.3, this can happen with benzo(a)pyrene 7,8-epoxide, which becomes oxidized to carcinogenic benzo(a)pyrene 7,8-diol-9,10-epoxide. The parent polycyclic aromatic hydrocarbon benzo(a)pyrene is classified as a procarcinogen, or precarcinogen, in that metabolic action is required to convert it to a species, in this case benzo(a)pyrene 7,8-diol-9,10-epoxide, which is carcinogenic as such. 

These studies demonstrated that DNA-binding can be a reliable probe of metabolic activation. In contrast to studies of metabolites per se, which usually involve large numbers of metabolite intermediates, DNA-binding monitors only chemically reactive metabolites. Also, if there is no selective repair of specific adducts, DNA-binding monitors the cumulative production of metabolites over time, while direct measurement of metabolites can show the metabolite spectrum only at the time observed. This can be particularly critical for studies of activation of complex chemicals such as polycyclic aromatic hydrocarbons whose primary metabolites are subject to secondary and tertiary metabolism (8). 

Kommaddi, R.P., Turman, C.M., Moorthy, B., Wang, L., Strobel, H.W., Ravindranath, V. (2007). An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA-reactive metabolites. J. Neurochem. 102 867-77. 

Synthesis and Reactivities of Aromatic Oxides. Certain optically active arene oxides, which are of biological significance as metabolites of polycyclic aromatic hydrocarbons (PAH), undergo spontaneous racemisation. The most plausible mechanism for this involves ring opening to the corresponding oxepins... 

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