An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo[a]pyrene 7,8-oxide

The (+) and (-)-enantiomers of benzo[α]pyrene 7,8-oxide are hydrated stereospecifically at C-8 to (-)- and (+)-trans-7,8-dihydroxy-7,8-dihydrobenzo(α)pyrene, respectively, by rat hepatic epoxide hydrolase. The (-)-enantiomer of benzo[a]pyrene 7,8-oxide is metabolized by microsomal epoxide hydrolase at a rate 3-to 4-fold greater than the (+)-enantiomer. At low conversion of racemic substrate, however, benzo[α]pyrene 7,8-oxide is metabolized to the dihydrodiol at a rate equal to that of the (+)-enantiomer. An analysis of the enantiomeric composition of the dihydrodiol formed from the racemic substrate revealed preferential formation of (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[α]pyrene. At low substrate conversion (<20% metabolism), the enantiomeric purity of the dihydrodiol was much higher than at high substrate conversion (>50% metabolism). Similar results were obtained with microsomes from hamster, rabbit, guinea pig, mouse, and human liver. These results indicate that epoxide hydrolase has a higher affinity for (+)-benzo[α]pyrene 7,8-oxide than for the (-)-enantiomer. The kinetics of hydration of (+)- and (-)-benzo[α]pyrene 7,8-oxide by purified epoxide hydrolase in detergent solution showed the (+)- and (-)-enantiomers to have apparent K(m) values of 1.7 and ≥20 μM, respectively. Tumorigenicity studies with benzo[α]pyrene 7,8-oxide on mouse skin and in newborn mice revealed that (+)-benzo[α]-pyrene 7,8 oxide, the metabolic precursor of the more tumorigenic (-)-7,8-dihydrodiol, is significantly more tumorigenic than the (-)-enantiomer. However, racemic benzo[α]pyrene 7,8-oxide was more tumorigenic than either enantiomer alone, indicating an enantiomeric synergism in the carcinogenicity of benzo[α]pyrene 7,8-oxide. The data are discussed in relation to the complete sequence of metabolic pathways leading to an ultimate carcinogen from benzo[α]pyrene.