TABLE 3

Milk thistle– and resveratrol–drug interaction liability in cell systems

Cell System	Preparation	Enzyme or Transporter	Substrate	Incubation Conditions	Metric/Outcome	Reference
Human hepatocytes	Silymarin	CYP3A4	Testosterone	48 h at 100 µM	50% ↓ in activity	Venkataramanan et al. (2000)
Human hepatocytes	Silymarin	UGT1A6/9	4-Methylumbelliferone	48 h at 100 µM	65% ↓ in activity	Venkataramanan et al. (2000)
Human hepatocytes	Silibinin	CYP1A2	NA	72 h at 100 µM	No change in mRNA or protein expression	Kosina et al. (2005)
Human hepatocytes	Silibinin	CYP3A4	NA	72 h at 100 µM	No change in mRNA or protein expression	Kosina et al. (2005)
Human hepatocytes	Silymarin	CYP2C9	Diclofenac	72 h at 100 µM	No change in activity	Doehmer et al. (2008)
Human hepatocytes	Silymarin	CYP3A4	Testosterone	72 h at 100 µM	No change in activity	Doehmer et al. (2008)
Human hepatocytes (three donors per enzyme)	Milk thistle extract	CYP1A2	7-Ethoxyresorufin	72 h at 50 µg/ml	1.1- to 8.5-fold ↑ in activity	Doehmer et al. (2011)
		CYP2B6	(S)-Mephenytoin		0.3- to 2.7-fold ↑ in activity
		CYP2C9	Diclofenac		0.7- to 1.6-fold ↑ in activity
		CYP2E1	Chlorzoxazone		2.0- to 3.0-fold ↑ in activity
		CYP3A4	Testosterone		0.4- to 1.3-fold ↑ in activity
Caco-2 cells	Silibinin	CYP3A4	NA	48 h at 10 µM	9% ↓ in protein	Budzinski et al. (2007)
Caco-2 cells	Silibinin	P-gp	NA	48 h at 10 µM	69% ↑ in protein	Budzinski et al. (2007)
Caco-2 cells	Silymarin	P-gp	Digoxin	1 h at 150 µM	23% ↑ in accumulation	Zhang and Morris (2003a)
Caco-2 cells	Silymarin	P-gp	Vinblastine	1 h at 150 µM	80% ↑ in accumulation	Zhang and Morris (2003a)
Caco-2 cells	Silibinin	CYP3A4	Cortisol	30 min	No change	Patel et al. (2004)
Caco-2 cells		P-gp	Ritonavir		No change in transport
MDR1-transfected MDCK cells		P-gp	Ritonavir		No change in transport
MDA435/LCC6 cells	Silymarin	P-gp	Daunomycin	2 h at 50 µM	4.5-fold ↑ in accumulation	Zhang and Morris (2003b)
Panc-1 cells	Silymarin	MRP1	Daunomycin	2 h at 100 µM	3.1-fold ↑ in accumulation	Nguyen et al. (2003)
Panc-1 cells	Silymarin	MRP1	Vinblastine	2 h at 100 µM	3.3-fold ↑ in accumulation	Nguyen et al. (2003)
BCRP overexpressing membrane vesicles	Milk thistle extract	BCRP	Methotrexate	2 min at 1000 µg/ml	45% ↓ in transport	Tamaki et al. (2010)
MCF-7 MX100 cells	Silymarin	BCRP	Mitoxantrone	15-min preincubation, 30-min coincubation	EC₅₀, 34 µM	Zhang et al. (2004)
BCRP-transfected MDCK cells	Silymarin	BCRP	Rosuvastatin	1 h	K_i, 98 µM	Deng et al. (2008)
OATP1B1-transfected Xenopus oocytes	Silymarin	OATP1B1	Rosuvastatin	30 min	K_i, 0.93 µM	Deng et al. (2008)
HEK293-OATP1B1	Silymarin	OATP1B1	Estradiol-17-β-glucuronide	3 min	IC₅₀, 1.3 µM	Kock et al. (2013)
HEK293-OATP1B3		OATP1B3	Estradiol-17-β-glucuronide		IC₅₀, 2.2 µM
MDCKII-OATP2B1		OATP2B1	Estrone-3-sulfate		IC₅₀, 0.3 µM
HepG2, MCF-7	trans-Resveratrol	CYP1A1	NA	6 h	Concentration-dependent ↓ in TCDD-induced CYP1A1 mRNA and 47% ↓ in basal CYP1A1 mRNA (HepG2), concentration-dependent ↓ in DMBA-induced CYP1A1 mRNA (MCF-7)	Ciolino et al. (1998) and Ciolino and Yeh (1999)
Human bronchial epithelial BEAS-2B and BEP2D cells	trans-Resveratrol	CYP1A1 and CYP1B1	Benzo[a]pyrene	24 or 72 h	56% ↓ CYP1A1 mRNA (24 h), 70% ↓ CYP1A1 mRNA (72 h)	Berge et al. (2004)
Caco-2 cells	trans-Resveratrol	UGT1A1	NA	72 h	4-fold ↑ in UGT1A1 mRNA	Iwuchukwu et al. (2011)

NA, not applicable.