Hydroperoxidation by cytochrome P-450 oxygenase: metabolism of 9-methylfluorene |
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| Authors: | C Chen T I Ruo D P Gurka |
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| Affiliation: | 1. Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (B.H.U.), Varanasi 221 005, U.P., India;2. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India;1. Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK;2. Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK;3. European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, UK;1. Department of Chemistry, Vanderbilt University, Nashville, TN 37212, USA;2. Center for Structural Biology, Vanderbilt University, Nashville, TN 37212, USA;3. Department of Biological Sciences, Vanderbilt University, Nashville, TN 37212, USA;4. Institute for Drug Discovery, Leipzig University Medical School, 04103 Leipzig, Germany |
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| Abstract: | 9-Methylfluorene was metabolized by rat liver microsomes to 9-hydroperoxy-9-methylfluorene and 9-hydroxy-9-methylfluorene. The results were confirmed by using a reconstituted cytochrome P-450 oxygenase system purified from phenobarbital-induced rat liver which established its involvement. SKF-525A strongly inhibited the formation of both oxygenation products. Cytochrome P-450 alone brought about the conversion of the hydroperoxide to its alcohol. NADPH augmented the peroxidative reaction, but the presence of NADPH-cytochrome P-450 reductase was without effect. Certain microsomal preparations and reconstituted enzyme yielded little or no detectable amounts of hydroperoxide. This was due to a too rapid conversion of the hydroperoxide to its alcohol. The addition of metyrapone, a compound that inhibited such conversion, resulted in accumulation of 9-hydroperoxy-9-methylfluorene for positive identification. Incubation of 9-methylfluorene with microsomes and NADPH resulted in covalent binding of its metabolite to microsomal proteins. Incubation of 14C-labeled 9-hydroperoxy-9-methylfluorene caused covalent binding of label to proteins, RNA, and DNA. |
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