Stereoselective metabolism of dibenz(a,h)anthracene to trans-dihydrodiols and their activation to bacterial mutagens.
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.
Platt
K L
KL
Institute of Toxicology, University of Mainz, Federal Republic of Germany.
Schollmeier
M
M
Frank
H
H
Oesch
F
F
D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D001551:Benz(a)Anthracenes; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; C026486:1,2,5,6-dibenzanthracene