title: The Binding of Silibinin, the Main Constituent of Silymarin, to Site I on Human Serum Albumin.
abstract: Silibinin is the main constituent of silymarin, an extract from the seeds of milk thistle (Silybum marianum). Because silibinin has many pharmacological activities, extending its clinical use in the treatment of a wider variety of diseases would be desirable. In this study, we report on the binding of silibinin to plasma proteins, an issue that has not previously been extensively studied. The findings indicated that silibinin mainly binds to human serum albumin (HSA). Mutual displacement experiments using ligands that primarily bind to sites I and II clearly revealed that silibinin binds tightly and selectively to site I (subsites Ia and/or Ic) of HSA, which is located in subdomain IIA. Thermodynamic analyses suggested that hydrogen bonding and van der Waals interactions are major contributors to silibinin-HSA interactions. Furthermore, the binding of silibinin to HSA was found to be decreased with increasing ionic strength and detergent concentration of the media, suggesting that electrostatic and hydrophobic interactions are involved in the binding. Trp214 and Arg218 were identified as being involved in the binding of silibinin to site I, based on binding experiments using chemically modified- and mutant-HSAs. In conclusion, the available evidence indicates that silibinin binds to the region close to Trp214 and Arg218 in site I of HSA with assistance by multiple forces and can displace site I drugs (e.g., warfarin or iodipamide), but not site II drugs (e.g., ibuprofen).
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University.
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Saori
authors.initials: S
authors.lastname: Minagoshi
authors.forename: Karin
authors.initials: K
authors.lastname: Kyubun
authors.forename: Makoto
authors.initials: M
authors.lastname: Anraku
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Miyamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.forename: Hakaru
authors.initials: H
authors.lastname: Seo
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
mesh_terms: D001665:Binding Sites; D041743:Herb-Drug Interactions; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D011485:Protein Binding; D012639:Seeds; D012709:Serum Albumin / Q000737:chemistry*; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry* / Q000493:pharmacokinetics; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D012709:Serum Albumin; D012838:Silymarin; D000077385:Silybin