The in vitro metabolic activation of dibenz[a,h]anthracene, catalyzed by rat liver microsomes and examined by 32P-postlabelling

Bisdihydrodiols, rather than dihydrodiol oxides, are the principal microsomal metabolites of tumorigenic trans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]anthracene

“…Thus the postulated reactivity of the ultimate mutagens of the three bisdihydrodiols was confirmed by the extent of DNA binding in mouse skin (42), which rose from no detectable binding in the case of DBA-3,4:12,13-bisdihydrodiol to weak binding in the case of DBA-3,4:8,9-bisdihydrodiol, reaching its highest value in the case of DBA-3,4:10,11bisdihydrodiol. Furthermore, DBA and DBA-3,4-dihydrodiol yielded the same pattern of DNA adducts when incubated with rat liver microsomes (38,39) or when applied to mouse skin in vivo (40), demonstrating anew the biological significance of the M-region dihydrodiol of DBA as precursor of its genotoxic metabolite(s). In both metabolizing systems DNA adducts based on bay-region dihydrodiol oxides were detected (38)(39)(40) and could be characterized ( 39), yet, especially in vivo, their amount was surpassed by more polar adducts (40).…”

“…Furthermore, DBA and DBA-3,4-dihydrodiol yielded the same pattern of DNA adducts when incubated with rat liver microsomes (38,39) or when applied to mouse skin in vivo (40), demonstrating anew the biological significance of the M-region dihydrodiol of DBA as precursor of its genotoxic metabolite(s). In both metabolizing systems DNA adducts based on bay-region dihydrodiol oxides were detected (38)(39)(40) and could be characterized ( 39), yet, especially in vivo, their amount was surpassed by more polar adducts (40). Remarkably, this could be shown not only with mouse skin (40) but also with human skin in culture (41).…”

“…Therefore, it will be interesting to determine the stereoselectivity in the metabolic conversion of enantiomeric DBA-3,4-dihydrodiol and to eluciate the role of the stereoisomers of the bisdihydrodiols in the genotoxicity of DBA. The relevance of the metabolic pathways elucidated in this study for the genotoxic activity of DBA has been furthermore ascertained by determination of the DNA binding in vitro (36,38,39) and in vivo (40)(41)(42). Thus the postulated reactivity of the ultimate mutagens of the three bisdihydrodiols was confirmed by the extent of DNA binding in mouse skin (42), which rose from no detectable binding in the case of DBA-3,4:12,13-bisdihydrodiol to weak binding in the case of DBA-3,4:8,9-bisdihydrodiol, reaching its highest value in the case of DBA-3,4:10,11bisdihydrodiol.…”