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SILYBIN INACTIVATES CYTOCHROMES P450 3A4 AND 2C9 AND INHIBITS MAJOR HEPATIC GLUCURONOSYLTRANSFERASES

Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan (C.S., U.M.K., P.F.H.); and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan (T.C.G., J.A.W.)

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 µM, a k_inact of 0.06 min^-1, and a t_1/2 of 14 min. Testosterone metabolism to 6-ß-hydroxytestosterone (P450 3A4) was also inactivated with a K_I of 166 µM, 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 µM, 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 IC₅₀ values of 1.4 µM, 28 µM, 20 µM, 92 µM, and 75 µM, 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.

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