The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin

Keishi Yamasaki, Hiroki Sato, Saori Minagoshi, Karin Kyubun, Makoto Anraku, Shigeyuki Miyamura, Hiroshi Watanabe, Kazuaki Taguchi, Hakaru Seo, Toru Maruyama, Masaki Otagiri

Research output: Contribution to journalArticle

4 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)310-317
Number of pages8
JournalBiological and Pharmaceutical Bulletin
Volume40
Issue number3
DOIs
Publication statusPublished - 2017 Jan 1
Externally publishedYes

Fingerprint

Silymarin
Serum Albumin
Milk Thistle
Iodipamide
silybin
Ibuprofen
Warfarin
Hydrogen Bonding
Static Electricity
Hydrophobic and Hydrophilic Interactions
Thermodynamics
Pharmaceutical Preparations
Detergents
Osmolar Concentration
Blood Proteins
Seeds
Pharmacology
Ligands

Keywords

  • Binding site
  • Human serum albumin (HSA)
  • Silibinin
  • Silymarin
  • Site I

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Yamasaki, K., Sato, H., Minagoshi, S., Kyubun, K., Anraku, M., Miyamura, S., ... Otagiri, M. (2017). The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin. Biological and Pharmaceutical Bulletin, 40(3), 310-317. https://doi.org/10.1248/bpb.b16-00790

The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin. / Yamasaki, Keishi; Sato, Hiroki; Minagoshi, Saori; Kyubun, Karin; Anraku, Makoto; Miyamura, Shigeyuki; Watanabe, Hiroshi; Taguchi, Kazuaki; Seo, Hakaru; Maruyama, Toru; Otagiri, Masaki.

In: Biological and Pharmaceutical Bulletin, Vol. 40, No. 3, 01.01.2017, p. 310-317.

Research output: Contribution to journalArticle

Yamasaki, K, Sato, H, Minagoshi, S, Kyubun, K, Anraku, M, Miyamura, S, Watanabe, H, Taguchi, K, Seo, H, Maruyama, T & Otagiri, M 2017, 'The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin', Biological and Pharmaceutical Bulletin, vol. 40, no. 3, pp. 310-317. https://doi.org/10.1248/bpb.b16-00790
Yamasaki, Keishi ; Sato, Hiroki ; Minagoshi, Saori ; Kyubun, Karin ; Anraku, Makoto ; Miyamura, Shigeyuki ; Watanabe, Hiroshi ; Taguchi, Kazuaki ; Seo, Hakaru ; Maruyama, Toru ; Otagiri, Masaki. / The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin. In: Biological and Pharmaceutical Bulletin. 2017 ; Vol. 40, No. 3. pp. 310-317.
@article{144292bc736146b38cfe21eb2321b50c,
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).",
keywords = "Binding site, Human serum albumin (HSA), Silibinin, Silymarin, Site I",
author = "Keishi Yamasaki and Hiroki Sato and Saori Minagoshi and Karin Kyubun and Makoto Anraku and Shigeyuki Miyamura and Hiroshi Watanabe and Kazuaki Taguchi and Hakaru Seo and Toru Maruyama and Masaki Otagiri",
year = "2017",
month = "1",
day = "1",
doi = "10.1248/bpb.b16-00790",
language = "English",
volume = "40",
pages = "310--317",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "3",

}

TY - JOUR

T1 - The binding of silibinin, the main constituent of silymarin, to site i on human serum albumin

AU - Yamasaki, Keishi

AU - Sato, Hiroki

AU - Minagoshi, Saori

AU - Kyubun, Karin

AU - Anraku, Makoto

AU - Miyamura, Shigeyuki

AU - Watanabe, Hiroshi

AU - Taguchi, Kazuaki

AU - Seo, Hakaru

AU - Maruyama, Toru

AU - Otagiri, Masaki

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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).

AB - 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).

KW - Binding site

KW - Human serum albumin (HSA)

KW - Silibinin

KW - Silymarin

KW - Site I

UR - http://www.scopus.com/inward/record.url?scp=85014353428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014353428&partnerID=8YFLogxK

U2 - 10.1248/bpb.b16-00790

DO - 10.1248/bpb.b16-00790

M3 - Article

VL - 40

SP - 310

EP - 317

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 3

ER -