C-7 configuration as one of determinants in taxanes metabolism by human cytochrome P450 enzymes.
Taxanes exhibit a high tendency to epimerize at C-7 under physiological conditions. This study aimed to investigate the composite effect of C-7 configuration and other substructural elements on the metabolic properties of taxanes. Cephalomannine, 7-epi-cephalomannine, 10-deacetyl-paclitaxel, and 7-epi-10-deacetyl-paclitaxel were chosen as model compounds. In human liver microsomes, 7-epi-cephalomannine was subject to C-13 lateral chain (M-1) and diterpenoid core monohydroxylation (M-2), mediated by cytochrome P450 (CYP) 3A4 and CYP2C8, respectively. However, only one 7-epi-10-deacetyl-paclitaxel metabolite (M), monohydroxylated at taxane ring by CYP2C8, was detected. In comparison with cephalomannine, the catalytic efficiency of CYP2C8 for 7-epi-cephalomannine was about five-fold higher due to the decreased K(m). Although CYP2C8 showed a high capacity for metabolizing 7-epi-10-deacetyl-paclitaxel, 10-deacetyl-paclitaxel was hardly metabolized under the identical incubation conditions. In conclusion, C-7 configuration represents one of the most important structural determinants in taxanes metabolism.
Zhang
Y-Y
YY
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Liu
Y
Y
Zhang
J-W
JW
Ge
G-B
GB
Liu
H-X
HX
Wang
L-M
LM
Sun
J
J
Yang
L
L
D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000378:metabolism*; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D043823:Taxoids / Q000737:chemistry* / Q000378:metabolism*
D001952:Bridged-Ring Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; C056348:cephalomannine; D003577:Cytochrome P-450 Enzyme System; D017239:Paclitaxel