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  • Title: Human hepatic cytochrome P-450 composition as probed by in vitro microsomal metabolism of warfarin.
    Author: Kaminsky LS, Dunbar DA, Wang PP, Beaune P, Larrey D, Guengerich FP, Schnellmann RG, Sipes IG.
    Journal: Drug Metab Dispos; 1984; 12(4):470-7. PubMed ID: 6148215.
    Abstract:
    Human liver microsomal fractions from 27 renal donors (tissue obtained post mortem) and from six cancer patients (tissue obtained during surgery) were used to investigate human hepatic cytochrome P-450 isozyme compositions. In vitro microsomal metabolism of the R and S enantiomers of warfarin to dehydrowarfarin and 4'-, 6-, 7-, 8-, and 10-hydroxywarfarin is catalyzed by cytochrome P-450 isozymes and was used as the basis for evaluating similarities and differences between human cytochrome P-450 isozyme compositions. The mean hepatic cytochrome P-450 concentration from postmortem samples was not significantly different from that of surgical patients (0.51 +/- 0.16 vs. 0.35 +/- 0.14 nmol/mg protein), but the NADPH-cytochrome P-450 reductase activity of the former was significantly higher than that of the latter (141 +/- 56 vs. 29 +/- 6 nmol cytochrome c reduced/min/mg protein). In general, the microsomal preparations were overall stereoselective for R warfarin metabolism. The stereoselectivities for formation of the individual metabolites of the R enantiomer were 6-, 8-, and 10-hydroxywarfarin and the S enantiomer were 4'- and 7-hydroxywarfarin. Of the 33 microsomal preparations, 21 exhibited qualitatively similar warfarin metabolite profiles with 6R- and 7S-hydroxywarfarin having the highest formation rates. Some of the preparations exhibited markedly different metabolite profiles, the most notable having 10R-hydroxywarfarin as the major metabolite. Based on the known warfarin metabolite profiles of five purified cytochrome P-450 isozymes, the isozyme composition of the microsomes can be estimated. The majority of the microsomal preparations apparently had similar isozyme compositions but some preparations were markedly different.
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