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Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2004 Jun; Vol. 32 (6), pp. 587-94. - Publication Year :
- 2004
-
Abstract
- Silybin, a major constituent of the milk thistle, is used to treat several liver disorders. Silybin inactivated purified, recombinant cytochromes P450 (P450) 3A4 and 2C9 in a mechanism-based manner. The inactivations were time-, concentration-, and NADPH-dependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl-)coumarin O-debenzylation activity (P450 3A4) was characterized by a K(I) of 32 microM, a k(inact) of 0.06 min(-1), and a t(1/2) of 14 min. Testosterone metabolism to 6-beta-hydroxytestosterone (P450 3A4) was also inactivated with a K(I) of 166 microM, a k(inact) of 0.08 min(-1), and a t(1/2) of 9 min. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified human P450 2C9 was inactivated with a K(I) of 5 microM, a k(inact) of 0.14 min(-1), and a t(1/2) of 7 min. Parallel loss of heme was observed with both P450s. Activity of both P450 enzymes was not recovered after removal of silybin either by dialysis or by spin gel filtration. In addition, silybin inhibited the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin catalyzed by recombinant hepatic UDP-glucuronosyltransferases (UGTs) 1A1, 1A6, 1A9, 2B7, and 2B15, with IC(50) values of 1.4 microM, 28 microM, 20 microM, 92 microM, and 75 microM, respectively. Silybin was a potent inhibitor of UGT1A1 and was 14- and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.
- Subjects :
- Aryl Hydrocarbon Hydroxylases isolation & purification
Aryl Hydrocarbon Hydroxylases metabolism
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System isolation & purification
Cytochrome P-450 Enzyme System metabolism
Glucuronosyltransferase metabolism
Heme metabolism
Kinetics
NADP
Plant Extracts pharmacology
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins metabolism
Silybin
Testosterone metabolism
Aryl Hydrocarbon Hydroxylases antagonists & inhibitors
Cytochrome P-450 Enzyme Inhibitors
Glucuronosyltransferase antagonists & inhibitors
Silymarin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0090-9556
- Volume :
- 32
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 15155549
- Full Text :
- https://doi.org/10.1124/dmd.32.6.587