HUMAN HEPATIC CYTOCHROME-P-450 COMPOSITION AS PROBED BY INVITRO MICROSOMAL METABOLISM OF WARFARIN

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (4) , 470-477
Abstract
Human liver microsomal fractions from 27 renal donors (tissue obtained post mortem) and from 6 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 post-mortem 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 per 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 5 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.