Stereoselective metabolism of dibenz(a,h)anthracene to trans-dihydrodiols and their activation to bacterial mutagens

Environ Health Perspect. 1990 Aug:88:37-41. doi: 10.1289/ehp.908837.

Abstract

Dibenz(a,h)anthracene (DBA), a carcinogenic, polycyclic aromatic hydrocarbon ubiquitous in the environment, is metabolized by the hepatic microsomal fraction of immature Sprague-Dawley rats pretreated with Aroclor 1254 to 27 ethyl acetate-extractable metabolites. More than half of these metabolites (51%) consisted of trans-1,2-; -3,4-; and -5,6-dihydrodiols including their identified secondary metabolites. The three trans-dihydrodiols (4.9, 15.8, and 0.6% of total metabolic conversion) were highly enriched in their R,R enantiomers (85, 71, and 98%) as determined by high performance liquid chromatography on suitable chiral stationary phases. This is explained on the basis of the stereoselective epoxidation of DBA by cytochrome P-450c (induced by Aroclor 1254) followed by regioselective hydration catalyzed by microsomal epoxide hydrolase. Determination of the bacterial mutagenicity by measuring the reversion rate of histidine-dependent Salmonella typhimurium TA100 to histidine prototrophy revealed marked differences in the mutagenicity of the enantiomers of the trans-dihydrodiols of DBA when activated by the same metabolizing system as used in the metabolism studies. In the case of trans-1,2- and -5,6-dihydrodiol, the S,S enantiomers were converted to more mutagenic metabolites than their corresponding optical antipodes, whereas in the case of trans-3,4-dihydrodiol it was the R,R enantiomer that produced the stronger mutagens. Therefore, both regio- and stereoselectivity of the metabolizing enzymes attribute to the dominant role of trans-3,4-dihydrodiol in the mutagenicity of DBA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benz(a)Anthracenes / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism
  • Epoxide Hydrolases / metabolism
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Mutagenicity Tests
  • Mutagens / metabolism*
  • Rats
  • Rats, Inbred Strains
  • Stereoisomerism

Substances

  • Benz(a)Anthracenes
  • Mutagens
  • Cytochrome P-450 Enzyme System
  • Epoxide Hydrolases
  • 1,2,5,6-dibenzanthracene