METABOLIC-ACTIVATION OF THE (-S,S-ENANTIOMERS AND (-)-R,R-ENANTIOMERSOF 11,12-DIHYDROXY-11,12-DIHYDRODIBEZO[ALPHA,L]PYRENE - STEREOSELECTIVITY, DNA ADDUCT FORMATION, AND MUTAGENICITY IN CHINESE-HAMSTER V79 CELLS())

Polycyclic aromatic hydrocarbons require metabolic activation in order to exert their biological activity initiated by DNA binding. The meta bolic pathway leading to bay or fjord region dihydrodiol epoxides as u ltimate mutagenic and/or carcinogenic metabolites is thought to play a dominant role. For dibenzo[a,l]pyrene, considered as the most potent carcinogenic polycyclic aromatic hydrocarbon, the formation of the fjo rd region syn- and/or anti-11,12-dihydrodiol 13,-14-epoxide (DB[a,l]PD E) diastereomers has been found to be the principal metabolic activati on pathway in cell cultures leading to DNA adducts. In order to furthe r elucidate the stereoselectivity involved in this activation pathway via the formation of the trans-11,12-dihydrodiol, we have synthesized the enantiomerically pure 11,12-dihydrodiols of dibenzo[a,l]pyrene and investigated their biotransformation in rodents. Incubations with liv er microsomes of Sprague-Dawley rats and CD-1 mice pretreated with Aro clor 1254 revealed that the enzymatic conversion to the fiord region D B[a,l]PDE strongly depends on the absolute configuration of the 11,12- dihydrodiol enantiomers. While oxidation at the 13,14-position of the (+)-(11S,12S)-dihydrodiol is limited to a small extent, the (-)-11R,12 R-enantiomer is metabolized to its fjord region dihydrodiol epoxides i n considerably higher amounts. Moreover, this substrate is transformed with high stereoselectivity to the corresponding (-)-antidihydrodiol epoxide by liver microsomes of Aroclor 1254-treated rodents. The metab olism results were in good accordance with the extent of stable adduct formation in calf thymus DNA as investigated by the P-32-postlabeling technique and with the mutagenicity in Chinese hamster V79 cells of t he two enantiomeric 11,1a-dihydrodiols mediated by hepatic postmitecho ndrial preparations of Aroclor 1254-treated rats. The results indicate that both genotoxic events occurred predominantly by the stereoselect ive activation of the (-)-(11R,12R)-dihydrodiol to the (-)-anti-DB[a,l ]PDE with R,S,S,R-configuration.