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The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes.
Chem Biol Interact 2017; 271:24-29CB

Abstract

Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B) on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be achieved in humans supplemented with orally administered milk thistle extracts due to the poor bioavailability of flavonolignans documented with most commercially available formulations.

Authors+Show Affiliations

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA; Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia. Electronic address: aa.albassam@psau.edu.sa.Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28457856

Citation

Albassam, Ahmed A., et al. "The Effect of Milk Thistle (Silybum Marianum) and Its Main Flavonolignans On CYP2C8 Enzyme Activity in Human Liver Microsomes." Chemico-biological Interactions, vol. 271, 2017, pp. 24-29.
Albassam AA, Frye RF, Markowitz JS. The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes. Chem Biol Interact. 2017;271:24-29.
Albassam, A. A., Frye, R. F., & Markowitz, J. S. (2017). The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes. Chemico-biological Interactions, 271, pp. 24-29. doi:10.1016/j.cbi.2017.04.025.
Albassam AA, Frye RF, Markowitz JS. The Effect of Milk Thistle (Silybum Marianum) and Its Main Flavonolignans On CYP2C8 Enzyme Activity in Human Liver Microsomes. Chem Biol Interact. 2017 Jun 1;271:24-29. PubMed PMID: 28457856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes. AU - Albassam,Ahmed A, AU - Frye,Reginald F, AU - Markowitz,John S, Y1 - 2017/04/27/ PY - 2017/01/24/received PY - 2017/04/27/accepted PY - 2017/5/2/pubmed PY - 2017/6/3/medline PY - 2017/5/2/entrez KW - Cytochrome P450 KW - Drug metabolism KW - Enzyme inhibition KW - Isosilybin KW - Milk thistle KW - Silybin KW - Silymarin SP - 24 EP - 29 JF - Chemico-biological interactions JO - Chem. Biol. Interact. VL - 271 N2 - Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B) on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be achieved in humans supplemented with orally administered milk thistle extracts due to the poor bioavailability of flavonolignans documented with most commercially available formulations. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/28457856/The_effect_of_milk_thistle__Silybum_marianum__and_its_main_flavonolignans_on_CYP2C8_enzyme_activity_in_human_liver_microsomes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(17)30083-2 DB - PRIME DP - Unbound Medicine ER -