Licorice (Glycyrrhiza inflata)
Cytochrome P450 inhibition by licorice species Glycyrrhiza inflata and fourteen licorice constituents CSV JSON

The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of botanically identified licorice species Glycyrrhiza inflata and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A was a mechanism-based inhibitor. The licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.

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1 . Inhibition of CYP2C8 by G. inflata Licorice extract (id=NPDI-SUW3zQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

amodiaquine

n-desethylamodiaquine

  • CYP2C8 4306333

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

1 µM

11 concentrations from 0.005–250 μg/mL

2 . Inhibition of CYP2B6 by G. inflata Licorice extract (id=NPDI-mWgNew)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

bupropion 750982

hydroxybupropion 4037950

  • CYP2B6 4308333

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

12 µM

11 concentrations from 0.005–250 μg/mL

3 . Inhibition of CYP2D6 by G. inflata Licorice extract (id=NPDI-1PLoEQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/ml

dextromethorphan 1119510

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

2.5 µM

11 concentrations from 0.005–250 μg/mL

4 . Inhibition of CYP2C19 by G. inflata Licorice extract (id=NPDI-hR5T0g)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

mephenytoin, (s)-

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

50 µM

11 concentrations from 0.005–250 μg/mL

5 . Inhibition of CYP3A4 by G. inflata Licorice extract (id=NPDI-pHgnHQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

midazolam 708298

1'-hydroxymidazolam

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

2.5 µM

11 concentrations from 0.005–250 μg/mL

6 . Inhibition of CYP1A2 by G. inflata Licorice extract (id=NPDI-x89xLA)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/ml

phenacetin 19033710

acetaminophen 1125315

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

100 µM

11 concentrations from 0.005–250 μg/mL

7 . Inhibition of CYP3A4 by G. inflata Licorice extract (id=NPDI-beIHRg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

testosterone

6beta-hydroxytestosterone

  • CYP3A4 4306811

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

50 µM

11 concentrations from 0.005–250 μg/mL

8 . Inhibition of CYP2C9 by G. inflata Licorice extract (id=NPDI-Y7VPTg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

> 100 µg/mL

tolbutamide

hydroxymethyltolbutamide

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

100 µM

11 concentrations from 0.005–250 μg/mL

9 . Negligible inhibition of CYP2E1 by G. inflata Licorice extract (id=NPDI-eDM7DQ)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used —

> 100 µg/ml

chloroxazone

6-hydroxychloroxazone

  • CYP2E1 4173608

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

15 µM

11 concentrations from 0.005–250 μg/mL

10 . Negligible inhibition of CYP2A6 by G. inflata Licorice extract (id=NPDI-13n6-Q)

In Vitro Enzyme Inhibition Experiment

Negligible Inhibition was detected.  Cutoff used —

> 100 µg/ml

coumarin 19008106

7-hydroxycoumarin

  • CYP2A6 4309826

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.2 mg/mL

10 min

NADPH

1.5 µM

11 concentrations from 0.005–250 μg/mL

1 . Chemical characterization of Licorice, Glycyrrhiza inflata (id=NPDI-l1_dTA)

Characterization of Material Study

Inhibition of CYP enzymes by glycycoumarin

Inhibition of CYP enzymes by glycyrrhetinic acid

Inhibition of CYP enzymes by isoliquiritigenin

Inhibition of CYP enzymes by licochalcone a

Results

% weight compound/weight extract

glabridin, licoricidin had quantities of 0 and were excluded from the results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Material Preparation

ethanol, isopropanol, water (90:5:5, v/v/v)

species checked with DNA barcoding, and comparison with voucher specimens at the Field Museum of Natural History, Chicago.

Mass Spectrometry Analysis

UHPLC-MS/MS