Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel.
The C-7 chiral centre in paclitaxel is subject to epimerization under physiological conditions, thus making 7-epi-paclitaxel as the principal degradant. This study was designed to characterize the cytochrome P450 (CYP) enzymes involved in 7-epi-paclitaxel metabolism, and to examine possible metabolic interactions that this C-7 epimer may have with paclitaxel. In human liver microsomes, 7-epi-paclitaxel was oxidized to two monohydroxylated metabolites while the metabolic sites occurred at the C-13 side-chain for M-1 and taxane core ring for M-2. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that M-1 was generated predominantly by CYP3A4 and M-2 by CYP2C8. Co-incubation of 7-epi-paclitaxel with paclitaxel in human liver microsomes resulted in potent inhibition of 6alpha-hydroxypaclitaxel formation (IC((50)) = 2.1 +/- 0.2 muM), thus decreasing the metabolic elimination of paclitaxel. In conclusion, both CYP3A4 and CYP2C8 play a major role in biotransformation of 7-epi-paclitaxel in human liver microsomes. The existence of epimeric interactions between paclitaxel and its degradant might be a noteworthy factor resulting in the complex pharmacokinetic profile of paclitaxel.
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
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Zhang
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Liu
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Zhang
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Ge
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Wang
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Sun
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Yang
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*
C111746:7-epipaclitaxel; D007527:Isoenzymes; D043823:Taxoids; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human