Dihydrodiolepoxides (BPDE) are reactive derivatives that appear to mediate the genotoxic effects of benzo[a]pyrene (BP) and several other polycyclic hydrocarbons. Their formation requires sequential epoxidation, hydration, and epoxidation steps. The first epoxidation step is catalyzed by cytochrome P-450 isoenzymes whereas the second is catalyzed by cytochromes P-450 and assorted species of oxygen radicals (in particular peroxyl radicals). The stereochemistry of epoxidation of the procarcinogen 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) is a useful tool with which to dissect the contributions of cytochrome P-450-dependent and independent pathways. [32P]-Postlabeling techniques were developed to analyze the diastereomeric composition of BPDE-deoxynucleoside-bis-phosphate adducts recovered from DNA of target tissues for BP tumorigenesis. Application of these techniques revealed that cytochrome P-450 is the major contributor to BPDE production in mouse skin in vivo. Following administration of BP or (+)-BP-7,8-diol to female CD-1 mice, only minor amounts of adducts derived from peroxyl radical epoxidation were detected. In contrast, pretreatment of the animals with the tumor promoter tetradecanoyl phorbol acetate (TPA) led to the formation of sizeable amounts of non-cytochrome P-450-dependent adducts following coincident administration of (+)-BP-7,8-diol with a second dose of TPA. The results demonstrate that although oxygen radicals appear to play a minor role in tumor initiation by BP, they may play a major role in tumor promotion by phorbol esters.
|Original language||English (US)|
|Number of pages||11|
|Journal||Princess Takamatsu symposia|
|State||Published - 1990|