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Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes. 1995

S Kumar, and S K Singh, and P L Kole, and S Elmarakby, and H C Sikka
Laboratory of Environmental Toxicology and Chemistry, State University of New York College, Buffalo 14222.

The carcinogen dibenz[a,h]acridine (DB[a,h]ACR is metabolized predominantly to trans-3,4-dihydroxy-3,4-dihydro-dibenz[a,h]acridine (DB[a,h]ACR-3,4-diol) and the proximate carcinogen trans-10,11-dihydroxy-10,11-dihydrodibenz[a,h]acridine (DB[a,h]ACR-10,11-diol) [Steward et al. (1987) Carcinogenesis, 8, 1043-1050]. In the present investigation, the stereoselectivity of rat liver enzymes in metabolism of DB[a,h]ACR to its 3,4-diol and 10,11-diol and of DB[a,h]ACR-10,11-diol enantiomers to their bay-region diol epoxides has been examined with liver microsomes from control and 3-methylcholanthrene-treated rats. Both microsomal preparations produced the major metabolites DB[a,h]ACR-3,4-diol and DB[a,h]ACR-10,11-diol containing predominantly R,R-enantiomers with 38-54% optical purity. Metabolism of (-)-(10R,11R)- and (+)-(10S,11S)-enantiomers of DB[a,h]ACR-10,11-diol by liver microsomes from control rats produced predominantly bay-region diol epoxides (46-59% of total metabolites), whereas very little bay-region diol epoxides (14-17% of total metabolites) were produced by liver microsomes from 3-methylcholanthrene-treated rats. The bay-region diol epoxides produced in these studies consisted of predominantly DB[a,h]ACR-10,11-trans-diol epoxide diastereomer in which the benzylic hydroxyl group and epoxide oxygen are trans. However, (-)-DB[a,h]ACR-10R,11R-diol, a major metabolite of DB[a,h]ACR, was metabolized by liver microsomes from 3-methylcholanthrene-treated rats to (+)-[8R,9S,10S,11R]-DB[a,h]ACR-10,11-trans-diol epoxide, a diastereomer which displayed high mutagenic activity in V79 cells, in an amount which was 6.5-fold greater than that of the corresponding cis-diol epoxide diastereomer. The relative amounts of trans-diol epoxide versus cis-diol epoxide in the mixture of bay-region diol epoxides produced from DB[a,h]ACR-10R,11R-diol and DB[a,h]ACR-10S,11R-diol with liver microsomes from control rats and from DB[a,h]ACR-10S,11S-diol with liver microsomes from 3-methylcholanthrene-treated rats were 1.7, 2.1 and 2.3 respectively.

UI MeSH Term Description Entries
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D002273 Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D004852 Epoxy Compounds Organic compounds that include a cyclic ether with three ring atoms in their structure. They are commonly used as precursors for POLYMERS such as EPOXY RESINS. Epoxide,Epoxides,Epoxy Compound,Oxiranes,Compound, Epoxy,Compounds, Epoxy
D000166 Acridines Compounds that include the structure of acridine. Acridine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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