An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo[a]pyrene 7,8-oxide.
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.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D002273:Carcinogens; D006224:Cricetinae; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012878:Skin Neoplasms / Q000139:chemically induced*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D002273:Carcinogens; C023393:benzo(a)pyrene 7,8-oxide; D004851:Epoxide Hydrolases; D010634:Phenobarbital