Stereoselective formation and hydration of benzo[c]phenanthrene 3,4- and 5,6-epoxide enantiomers by rat liver microsomal enzymes |
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| Authors: | S K Yang M Mushtaq H B Weems |
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| Institution: | 1. Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, PR China;2. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China;1. College of Chemistry, Electron Microscopy Center, Jilin University, Changchun 130012, PR China;2. Department of Chemistry and the Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712-0165, USA;3. State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Technology, Jilin University, Changchun 130012, PR China;4. School of Physics and Electronic Information, Yan’an University, Yan’an 716000, PR China;1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People’s Republic of China;2. Nanjing Sanhome Pharmaceutical Co. Ltd, No. 99, West Yunlianghe Road, Jiangning District, Nanjing, 210049, People’s Republic of China;1. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK;2. Programa de Pós-Graduação em Medicina Tropical do Instituto de Medicina Tropical da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar 470, 05403-000, São Paulo, Brazil;3. Centre for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo 351, 01246-000, São Paulo, Brazil |
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| Abstract: | The K-region 5,6-epoxides, formed in the metabolism of benzoc]phenanthrene (BcPh) in the presence of an epoxide hydrolase inhibitor 3,3,3-trichloropropylene 1,2-oxide (TCPO) by liver microsomes from untreated, phenobarbital-treated, 3-methylcholanthrene-treated, and polychlorinated biphenyls (Aroclor 1254)-treated rats of the Sprague-Dawley and the Long-Evans strains, were found by chiral stationary phase high-performance liquid chromatography analyses to be enriched (58-72%) in the 5S, 6R enantiomer. In the absence of TCPO, the metabolically formed BcPh trans-5,6-dihydrodiol was enriched (78-86%) in the 5S,6S enantiomer. The major enantiomer of the BcPh 3,4-epoxide metabolite was found to be enriched in the 3S,4R enantiomer which undergoes racemization under the experimental conditions. The major enantiomer of the 5,6-dihydrodiol metabolite was elucidated by the exciton chirality circular dichroism (CD) method to have a 5S,6S absolute stereochemistry. Absolute configurations of enantiomeric methoxylation products derived from each of the two BcPh 5,6-epoxide enantiomers. Optically pure BcPh 5S,6R-epoxide was enzymatically hydrated exclusively at the C6 position to form an optically pure BcPh 5S,6S-dihydrodiol. However, optically pure BcPh 5R,6S-epoxide was hydrated at both C5 and C6 positions to form a BcPh trans-5,6-dihydrodiol with a (5S,6S):(5R,6R) enantiomer ratio of 32:68. |
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