Goldenseal (Hydrastis canadensis) 43525850
An in vitro Evaluation of Cytochrome P450 Inhibition and P-Glycoprotein Interaction with Goldenseal, Ginkgo biloba, Grape Seed, Milk Thistle, and Ginseng Extracts and Their Constituents CSV JSON

Drug-herb interactions can result from the modulation of the activities of cytochrome P450 (P450) and/or drug transporters. The effect of extracts and individual constituents of goldenseal, Ginkgo biloba (and its hydrolyzate), grape seed, milk thistle, and ginseng on the activities of cytochrome P450 enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes were determined using enzyme-selective probe substrates, and their effect on human P-glycoprotein (Pgp) was determined using a baculovirus expression system by measuring the verapamil-stimulated, vanadate-sensitive ATPase activity. Extracts were analyzed by HPLC to standardize their concentration(s) of constituents associated with the pharmacological activity, and to allow comparison of their effects on P450 and Pgp with literature values. Many of the extracts/constituents exerted > or = 50 % inhibition of P450 activity. These include those from goldenseal (normalized to alkaloid content) inhibiting CYP2C8, CYP2D6, and CYP3A4 at 20 microM, ginkgo inhibiting CYP2C8 at 10 microM, grape seed inhibiting CYP2C9 and CYP3A4 at 10 microM, milk thistle inhibiting CYP2C8 at 10 microM, and ginsenosides F1 and Rh1 (but not ginseng extract) inhibiting CYP3A4 at 10 microM. Goldenseal extracts/constituents (20 microM, particularly hydrastine) and ginsenoside Rh1 stimulated ATPase at about half of the activity of the model substrate, verapamil (20 microM). The data suggest that the clearance of a variety of drugs may be diminished by concomitant use of these herbs via inhibition of P450 enzymes, but less so by Pgp-mediated effects.

PMID: 17611934

17611934

1 . 1A2 Inhibition by Hydrastine (id=NPDI-59mQTg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

acetanilide

hydrastine

acetaminophen 1125315

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

2 . 2D6 Inhibition by Aq GS Extract (id=NPDI-IdieOw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

dextromethorphan 1119510

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

3 . 2D6 Inhibition by Berberine (id=NPDI-cRrAsg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

dextromethorphan 1119510

berberine 19012197

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

4 . 2D6 Inhibition by Ethanolic GS Extract (id=NPDI-PqZKVg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

dextromethorphan 1119510

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

5 . 2C19 Inhibition by Aq GS Extract (id=NPDI-0_ey6g)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

mephenytoin, (s)-

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

6 . 2C19 Inhibition by Ethanolic GS Extract (id=NPDI-3QKJaw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

mephenytoin, (s)-

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

7 . 2C19 Inhibition by Hydrastine (id=NPDI-6cuc3g)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

mephenytoin, (s)-

hydrastine

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate from Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

8 . 3A4 Inhibition by Aq GS Extract (MDZ) (id=NPDI-Z0x9xQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

midazolam 708298

1'-hydroxymidazolam

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

9 . 3A4 Inhibition by Ethanolic GS Extract (MDZ) (id=NPDI-cnkDpg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

midazolam 708298

1'-hydroxymidazolam

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

10 . 3A4 Inhibition by Hydrastine (MDZ) (id=NPDI-_UID1w)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

midazolam 708298

hydrastine

1'-hydroxymidazolam

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

11 . 2E1 Inhibition by Berberine (id=NPDI-ij84RA)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

p-nitrophenol

berberine 19012197

4-nitrophenyl sulfate

  • CYP2E1 4173608

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

12 . 2C8 Inhibition by Ethanolic GS Extract (id=NPDI-cesmqQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

paclitaxel

6-alpha-hydroxy paclitaxel

  • CYP2C8 4306333

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

13 . 2C8 Inhibition by Hydrastine (id=NPDI-VqNO0Q)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

paclitaxel

hydrastine

6-alpha-hydroxy paclitaxel

  • CYP2C8 4306333

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate of inhibition Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

14 . 3A4 Inhibition by Aq GS Extract (Testosterone) (id=NPDI-cYwbww)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

testosterone

6beta-hydroxytestosterone

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

15 . 3A4 Inhibition by Berberine (Testosterone) (id=NPDI-1ijwVg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

testosterone

berberine 19012197

6beta-hydroxytestosterone

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Estimate from Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

16 . 3A4 Inhibition by Ethanolic GS Extract (Testosterone) (id=NPDI-ibIkjQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

testosterone

6beta-hydroxytestosterone

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

17 . 3A4 Inhibition by Hydrastine (Testosterone) (id=NPDI-5wiIYg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — not specified

testosterone

hydrastine

6beta-hydroxytestosterone

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

18 . 1A2 Inhibition by Ethanolic GS Extract (id=NPDI-oVpWlA)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

acetanilide

acetaminophen 1125315

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

19 . 2D6 Inhibition by Hydrastine (id=NPDI-6gn9Dg)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

dextromethorphan 1119510

hydrastine

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

20 . 2C19 Inhibition by Berberine (id=NPDI-c2kfPA)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

mephenytoin, (s)-

berberine 19012197

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

estimate from Fig 1 at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

21 . 2E1 Inhibition by Hydrastine (id=NPDI-NNibEQ)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

p-nitrophenol

hydrastine

4-nitrophenyl sulfate

  • CYP2E1 4173608

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

22 . 2C8 Inhibition by Aq GS Extract (id=NPDI-37V97Q)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

paclitaxel

6-alpha-hydroxy paclitaxel

  • CYP2C8 4306333

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

23 . 2C8 Inhibition by Berberine (id=NPDI-2kECKw)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

paclitaxel

berberine 19012197

6-alpha-hydroxy paclitaxel

  • CYP2C8 4306333

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

24 . 2C9 Inhibition by Ethanolic GS Extract (id=NPDI-uBMfpQ)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

tolbutamide

hydroxymethyltolbutamide

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 Estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM

25 . 2C9 Inhibition by Hydrastine (id=NPDI-dgm1Ww)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used — not specified

tolbutamide

hydrastine

hydroxymethyltolbutamide

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Fig 1 estimate at 20 μM

Sample Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

In-house preparation

HHM-247 and HHM-258

15 min

NADPH

10 min

No NADPH with precipitant

1 or 20 μM