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Drug Metabolism and Disposition Fast Forward
First published on August 1, 2007; DOI: 10.1124/dmd.107.016410

0090-9556/07/3511-2035-2039$20.00
DMD 35:2035-2039, 2007

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Silybin Is Metabolized by Cytochrome P450 2C8 in Vitro

Petra Jancová, Eva Anzenbacherová, Barbora Papousková, Karel Lemr, Pavla Luzná, Alena Veinlichová, Pavel Anzenbacher, and Vilím Simánek

Faculty of Medicine, Department of Medical Chemistry and Biochemistry (P.J., E.A., V.S.) and Department of Pharmacology (P.L., A.V., P.A.), Faculty of Medicine, and Department of Analytical Chemistry (B.P., K.L.), Faculty of Sciences, Palacky University at Olomouc, Olomouc, Czech Republic

Silybin (a flavonolignan, the main component of silymarin, an extract from the seeds of Silybum marianum) has been used to date mostly as a hepatoprotectant. However, it also has other interesting activities, e.g., anticancer and hypocholesterolemic effects. It is also known that silybin can inhibit the activities of the cytochrome P450 (P450) enzymes. In this study, a weak interaction of silybin with human microsomal CYP2E1, 2A6, 2B6, 2C19, and 2D6 (IC50 ≥ 250 µM) was found; a moderate inhibition was observed for CYP1A2 and 2C8. The most prominent inhibition effect was found with CYP3A4 and CYP2C9 (IC50 ≤ 50 µM). Using mass spectometry detection, production of O-demethylated (the main metabolite) as well as hydroxylated derivatives of silybin formed by P450 enzymes was detected. The effect of different P450 inhibitors on the formation of O-demethylated product was also studied. In particular, a relatively specific inhibitor of CYP2C8 (quercetin) markedly inhibited the formation of this metabolite. With the help of recombinant enzymes (bactosomes), it was confirmed that the CYP2C8 enzyme is responsible for the reaction leading to O-demethylated silybin.

Address correspondence to: Dr. Eva Anzenbacherová, Palacky University at Olomouc, Faculty of Medicine and Dentistry, Department of Medical Chemistry and Biochemistry, Hnevotínská 3, 775 15 Olomouc, Czech Republic. E-mail: anzeneva{at}tunw.upol.cz




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S. R. Miranda, J. K. Lee, K. L. R. Brouwer, Z. Wen, P. C. Smith, and R. L. Hawke
Hepatic Metabolism and Biliary Excretion of Silymarin Flavonolignans in Isolated Perfused Rat Livers: Role of Multidrug Resistance-Associated Protein 2 (Abcc2)
Drug Metab. Dispos., November 1, 2008; 36(11): 2219 - 2226.
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