Enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo(a)pyrene 7,8-oxide

Journal Article · Fri Oct 10 04:00:00 EDT 1980 · J. Biol. Chem.; (United States)

OSTI ID:6816857

Levin, W; Buening, M K; Wood, A W

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 K/sub m/ values of 1.7 and greater than or equal to 20 ..mu..m, 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 benzol(a)pyrene 7,8-oxide.

• Research Organization: Hoffman-LaRoche, Inc., Nutley, NJ
• OSTI ID: 6816857
• Journal Information: J. Biol. Chem.; (United States), Journal Name: J. Biol. Chem.; (United States) Vol. 255:19; ISSN JBCHA
• Country of Publication: United States
• Language: English

Related Subjects

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59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
ANIMALS
AROMATICS
BENZOPYRENE
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL PATHWAYS
BODY
CARCINOGENESIS
CELL CONSTITUENTS
CONDENSED AROMATICS
DATA
DIGESTIVE SYSTEM
DISEASES
ENANTIOMORPHS
ENZYMES
EPOXIDES
EXPERIMENTAL DATA
GLANDS
GLYCOLS
GUINEA PIGS
HAMSTERS
HYDROCARBONS
HYDROLASES
HYDROXY COMPOUNDS
INFORMATION
KINETICS
LABELLED COMPOUNDS
LIVER
MAMMALS
MAN
METABOLIC ACTIVATION
METABOLISM
MICE
MICROSOMES
NEOPLASMS
NUMERICAL DATA
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
PATHOGENESIS
PHENANTHRENE
PRIMATES
RABBITS
RACEMATES
RATS
REACTION KINETICS
RODENTS
SKIN
SYNERGISM
TRITIUM COMPOUNDS
VERTEBRATES