Abstract
The enantiomers of a trans-5,6-dihydrodiol formed in the metabolism of 7,12-dimethylbenz[a]anthracene by rat liver microsomes (microsomal fractions) were resolved by chiral stationary-phase high-performance liquid chromatography. The major 7,12-dimethylbenz[a]anthracene trans-5,6-dihydrodiol enantiomer and its hydrogenation product 5,6,8,9,10,11-hexahydro-trans-5,6-diol were found to have 5S,6S absolute configurations by the exciton chirality c.d. method. The R,R/S,S enantiomer ratios of 7,12-dimethylbenz[a]anthracene trans-5,6-dihydrodiol formed in the metabolism of 7,12-dimethylbenz[a]anthracene by liver microsomes from untreated, 3-methylcholanthrene-treated and phenobarbital-treated male Sprague-Dawley rats were found to be 11:89, 6:94, and 5:95 respectively. These findings and those reported previously on the metabolic formations of trans-5,6-dihydrodiols from 7-methylbenz[a]anthracene and 12-methylbenz[a]anthracene suggest that the 12-methyl group in 7,12-dimethylbenz[a]anthracene plays an important role in determining the stereoselective metabolism at the K-region 5,6-double bond. Furthermore, the finding that formation of 5S,6S-dihydrodiol as the predominant enantiomer was not significantly affected by the isoenzymic composition of cytochrome P-450 present in microsomes prepared from the livers of the rats pretreated with the different inducing agents indicates that the stereoselectivity depends on the substrate metabolized rather than on the precise nature of the metabolizing-enzyme system.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Akhtar M. N., Boyd D. R., Thompson N. J., Koreeda M., Gibson D. T., Mahadevan V., Jerina D. M. Absolute sterochemistry of the dihydroanthracene-cis- and -trans-1,2-diols produced from anthracene by mammals and bacteria. J Chem Soc Perkin 1. 1975;(23):2506–2511. [PubMed] [Google Scholar]
- Buhler D. R., Unlü F., Thakker D. R., Slaga T. J., Conney A. H., Wood A. W., Chang R. L., Levin W., Jerina D. M. Effect of a 6-fluoro substituent on the metabolism and biological activity of benzo(a)pyrene. Cancer Res. 1983 Apr;43(4):1541–1549. [PubMed] [Google Scholar]
- Chiu P. L., Fu P. P., Yang S. K. Stereoselectivity of rat liver microsomal enzymes in the metabolism of 7-fluorobenz(a)anthracene and mutagenicity of metabolites. Cancer Res. 1984 Feb;44(2):562–570. [PubMed] [Google Scholar]
- Chou M. W., Chiu P. L., Fu P. P., Yang S. K. The effect of enzyme induction on the stereoselective metabolism of optically pure (-)1R,2R- and (+)1S,2S-dihydroxy-1,2-dihydrobenz-[a]anthracenes to vicinal 1,2-dihydrodiol 3,4-epoxides by rat liver microsomes. Carcinogenesis. 1983;4(5):629–638. doi: 10.1093/carcin/4.5.629. [DOI] [PubMed] [Google Scholar]
- Chou M. W., Yang S. K. Combined reversed-phase and normal-phase high-performance liquid chromatography in the purification and identification of 7,12-dimethylbenz[a]anthracene metabolites. J Chromatogr. 1979 Dec 20;185:635–654. doi: 10.1016/s0021-9673(00)85637-x. [DOI] [PubMed] [Google Scholar]
- Fu P. P., Chou M. W., Yang S. K. In vitro metabolism of 12-methylbenz(A)anthracene: effect of the methyl group on the stereochemistry of a 5,6-dihydrodiol metabolite. Biochem Biophys Res Commun. 1982 Jun 15;106(3):940–946. doi: 10.1016/0006-291x(82)91801-0. [DOI] [PubMed] [Google Scholar]
- Fu P. P., Yang S. K. Stereoselective metabolism of 6-bromobenzo[a]pyrene by rat liver microsomes: absolute configuration of trans-dihydrodiol metabolites. Biochem Biophys Res Commun. 1982 Dec 15;109(3):927–934. doi: 10.1016/0006-291x(82)92029-0. [DOI] [PubMed] [Google Scholar]
- Fu P. P., Yang S. K. Stereoselective metabolism of 7-bromobenz[a]anthracene by rat liver microsomes: absolute configurations of trans-dihydrodiol metabolites. Carcinogenesis. 1983 Aug;4(8):979–984. doi: 10.1093/carcin/4.8.979. [DOI] [PubMed] [Google Scholar]
- Harvey R. G., Goh S. H., Cortez C. "K-region" oxides and related oxidized metabolites of carcinogenic aromatic hydrocarbons. J Am Chem Soc. 1975 Jun 11;97(12):3468–3479. doi: 10.1021/ja00845a032. [DOI] [PubMed] [Google Scholar]
- Huberman E., Yang S. K., McCourt D. W., Gelboin H. V. Mutagenicity to mammalian cells in culture by (+) and (-) trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrenes and the hydrolysis and reduction products of two stereoisomeric benzo(a)pyrene 7,8-diol-9,10-epoxides. Cancer Lett. 1978 Jan;4(1):35–43. doi: 10.1016/s0304-3835(78)93247-0. [DOI] [PubMed] [Google Scholar]
- Jerina D. M., Daly J. W. Arene oxides: a new aspect of drug metabolism. Science. 1974 Aug 16;185(4151):573–582. doi: 10.1126/science.185.4151.573. [DOI] [PubMed] [Google Scholar]
- Jerina D. M., Selander H., Yagi H., Wells M. C., Davey J. F., Mahadevan V., Gibson D. T. Dihydrodiols from anthracene and phenanthrene. J Am Chem Soc. 1976 Sep 15;98(19):5988–5996. doi: 10.1021/ja00435a035. [DOI] [PubMed] [Google Scholar]
- Levin W., Chang R. L., Wood A. W., Yagi H., Thakker D. R., Jerina D. M., Conney A. H. High stereoselectivity among the optical isomers of the diastereomeric bay-region diol-epoxides of benz(a)anthracene in the expression of tumorigenic activity in murine tumor models. Cancer Res. 1984 Mar;44(3):929–933. [PubMed] [Google Scholar]
- Lu A. Y., West S. B. Multiplicity of mammalian microsomal cytochromes P-45. Pharmacol Rev. 1979 Dec;31(4):277–295. [PubMed] [Google Scholar]
- Miura R., Honmaru S., Nakazaki M. The absolute configurations of the metabolites of naphthalene and phenanthrene in mammalian systems. Tetrahedron Lett. 1968 Oct;(50):5271–5274. doi: 10.1016/s0040-4039(00)89839-1. [DOI] [PubMed] [Google Scholar]
- Sims P., Grover P. L. Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. Adv Cancer Res. 1974;20:165–274. doi: 10.1016/s0065-230x(08)60111-6. [DOI] [PubMed] [Google Scholar]
- Slaga T. J., Bracken W. J., Gleason G., Levin W., Yagi H., Jerina D. M., Conney A. H. Marked differences in the skin tumor-initiating activities of the optical enantiomers of the diastereomeric benzo(a)pyrene 7,8-diol-9,10-epoxides. Cancer Res. 1979 Jan;39(1):67–71. [PubMed] [Google Scholar]
- Thakker D. R., Levin W., Yagi H., Tada M., Ryan D. E., Thomas P. E., Conney A. H., Jerina D. M. Stereoselective metabolism of the (+)- and (-)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene by rat liver microsomes and by a purified and reconstituted cytochrome P-450 system. J Biol Chem. 1982 May 10;257(9):5103–5110. [PubMed] [Google Scholar]
- Thakker D. R., Levin W., Yagi H., Turujman S., Kapadia D., Conney A. H., Jerina D. M. Absolute stereochemistry of the trans-dihydrodiols formed from benzo[a]anthracene by liver microsomes. Chem Biol Interact. 1979 Oct;27(2-3):145–161. doi: 10.1016/0009-2797(79)90122-4. [DOI] [PubMed] [Google Scholar]
- Thakker D. R., Yagi H., Akagi H., Koreeda M., Lu A. H., Levin W., Wood A. W., Conney A. H., Jerina D. M. Metabolism of benzo[a]pyrene. VI. Stereoselective metabolism of benzo[a]pyrene and benzo[a]pyrene 7,8-dihydrodiol to diol epoxides. Chem Biol Interact. 1977 Mar;16(3):281–300. doi: 10.1016/0009-2797(77)90108-9. [DOI] [PubMed] [Google Scholar]
- Weems H. B., Yang S. K. Resolution of optical isomers by chiral high-performance liquid chromatography: separation of dihydrodiols and tetrahydrodiols of benzo[a]pyrene and benz[a]anthracene. Anal Biochem. 1982 Sep 1;125(1):156–161. doi: 10.1016/0003-2697(82)90397-9. [DOI] [PubMed] [Google Scholar]
- Yang S. K., Chou M. W., Fu P. P., Wislocki P. G., Lu A. H. Epoxidation reactions catalyzed by rat liver cytochromes P-450 and P-448 occur at different faces of the 8,9-double bond of 8-methylbenz[a]anthracene. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6802–6806. doi: 10.1073/pnas.79.22.6802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang S. K., Fu P. P. Stereoselective metabolism of 7-methylbenz[a]anthracene: absolute configuration of five dihydrodiol metabolites and the effect of dihydrodiol conformation on circular dichroism spectra. Chem Biol Interact. 1984 Apr;49(1-2):71–88. doi: 10.1016/0009-2797(84)90053-x. [DOI] [PubMed] [Google Scholar]
- Yang S. K. The absolute stereochemistry of the major trans-dihydrodiol enantiomers formed from 11-methylbenz[a]anthracene by rat liver microsomes. Drug Metab Dispos. 1982 May-Jun;10(3):205–211. [PubMed] [Google Scholar]