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.
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/6/1
Y1 - 2017/6/1
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.
AB - 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.
KW - Cytochrome P450
KW - Drug metabolism
KW - Enzyme inhibition
KW - Isosilybin
KW - Milk thistle
KW - Silybin
KW - Silymarin
UR - http://www.scopus.com/inward/record.url?scp=85018401529&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2017.04.025
DO - 10.1016/j.cbi.2017.04.025
M3 - Article
C2 - 28457856
AN - SCOPUS:85018401529
SN - 0009-2797
VL - 271
SP - 24
EP - 29
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
ER -