Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities.
Silybin and related flavonolignans form a major part of the Silybum marianum extract, silymarin, which has been used to treat liver diseases for hundreds of years. Although regarded as safe, many of the extract constituents remain thus far untested for their possible effects on liver biotransformation enzymes. Cytochromes P450 (CYP) are very important in this regard. We tested the effect of four flavonolignans: silybin, its hemisynthetic derivative dehydrosilybin, silydianin, and silycristin on three specific CYP activities: bufuralol 1'-hydroxylation (CYP2D6), p-nitrophenol hydroxylation (CYP2E1), and nifedipine oxidation (CYP3A4). All flavonolignans displayed dose-dependent inhibition of these activities with IC(50) values in the micromolar range. The inhibition was competitive or mixed as revealed by double reciprocal plots of kinetic experiments. However, the inhibition is not considered to be relevant for therapy because physiological concentrations of the individual flavonolignans do not exceed 0.5 microM. The data support the use of the extract as a dietary supplement.
Zuber
Roman
R
Faculty of Chemical Technology, University of Pardubice, Nám. Cs. Legií 565, 532 10 Pardubice, Czech Republic.
Modrianský
Martin
M
Dvorák
Zdenek
Z
Rohovský
Petr
P
Ulrichová
Jitka
J
Simánek
Vilím
V
Anzenbacher
Pavel
P
D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D020944:Silybum marianum; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D005419:Flavonoids; D010936:Plant Extracts; D012838:Silymarin; D000077385:Silybin; C015505:silidianin; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C015504:silychristin