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

W. Levin, M. K. Buening, A. W. Wood, R. L. Chang, B. Kedzierski, D. R. Thakker, D. R. Boyd, G. S. Gadaginamath, R. N. Armstrong, H. Yagi, J. M. Karle, T. J. Slaga, D. M. Jerina, A. H. Conney

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83 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9067-9074
Number of pages8
JournalJournal of Biological Chemistry
Volume255
Issue number19
StatePublished - Dec 1 1980
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Levin, W., Buening, M. K., Wood, A. W., Chang, R. L., Kedzierski, B., Thakker, D. R., Boyd, D. R., Gadaginamath, G. S., Armstrong, R. N., Yagi, H., Karle, J. M., Slaga, T. J., Jerina, D. M., & Conney, A. H. (1980). An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo[a]pyrene 7,8-oxide. Journal of Biological Chemistry, 255(19), 9067-9074.