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J. Biol. Chem., Vol. 255, Issue 19, 9067-9074, 10, 1980

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

W Levin, MK Buening, AW Wood, RL Chang, B Kedzierski, DR Thakker, DR Boyd, GS Gadaginamath, RN Armstrong, H Yagi, JM Karle, TJ Slaga, DM Jerina and AH Conney

The (+)- and (-)-enantiomers of benzo[a]pyrene 7,8-oxide are hydrated stereospecifically at C-8 to (-)- and (+)-trans-7,8-dihydroxy-7,8- dihydrobenzo[a]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[a]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-[a]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[a]pyrene 7,8-oxide than for the (-)-enantiomer. The kinetics of hydration of (+)- and (-)-benzo[a]pyrene 7,8-oxide by purified epoxide hydrolase in detergent solution showed the (+)- and (- )-enantiomers to have apparent Km values of 1.7 and greater than or equal to 20 microM, respectively. Tumorigenicity studies with benzo[a]pyrene 7,8-oxide on mouse skin and in newborn mice revealed that (+)-benzo[a]pyrene 7,8-oxide, the metabolic precursor of the more tumorigenic (-)-7,8-dihydrodiol, is significantly more tumorigenic than the (-)-enantiomer. However, racemic benzo[a]pyrene 7,8-oxide was more tumorigenic than either enantiomer alone, indicating an enantiomeric synergism in the carcinogenicity of benzo[a]pyrene 7,8-oxide. The data are discussed in relation to the complete sequence of metabolic pathways leading to an ultimate carcinogen from benzo[a]pyrene.
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