Cannabis (Cannabis sativa)
Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes
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In this study, tetrahydrocannabinols (THCs) were mainly oxidized at the 11-position and allylic sites at the 7α-position for Δ8-THC and the 8β-position for Δ9-THC by human hepatic microsomes. Cannabinol (CBN) was also mainly metabolized to 11-hydroxy-CBN and 8-hydroxy-CBN by the microsomes. The 11-hydroxylation of three cannabinoids by the microsomes was markedly inhibited by sulfaphenazole, a selective inhibitor of CYP2C enzymes, while the hydroxylations at the 7α-(Δ8-THC), 8β-(Δ9-THC) and 8-positions (CBN) of the corresponding cannabinoids were highly inhibited by ketoconazole, a selective inhibitor of CYP3A enzymes. Human CYP2C9-Arg expressed in the microsomes of human B lymphoblastoid cells efficiently catalyzed the 11-hydroxylation of Δ8-THC (7.60 nmol/min/nmol CYP), Δ9-THC (19.2 nmol/min/nmol CYP) and CBN (6.62 nmol/min/nmol CYP). Human CYP3A4 expressed in the cells catalyzed the 7α-(5.34 nmol/min/nmol CYP) and 7β-hydroxylation (1.39 nmol/min/nmol CYP) of Δ8-THC, the 8β-hydroxylation (6.10 nmol/min/nmol CYP) and 9α,10α-epoxidation (1.71 nmol/min/nmol CYP) of Δ9-THC, and the 8-hydroxylation of CBN (1.45 nmol/min/nmol CYP). These results indicate that CYP2C9 and CYP3A4 are major enzymes involved in the 11-hydroxylation and the 8-(or the 7-) hydroxylation, respectively, of the cannabinoids by human hepatic microsomes. In addition, CYP3A4 is a major enzyme responsible for the 7α- and 7β-hydroxylation of Δ8-THC, and the 9α,10α-epoxidation of Δ9-THC.
1 . Inhibition of 8-hydroxylation of cannabinol by ketoconazole (id=NPDI-I4dv_g)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
2 . Inhibition of 11-hydroxylation of cannabinol by sulfaphenazole (id=NPDI-8flCOQ)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not provided
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM
3 . Inhibition of 7-alpha-hydroxylation of delta-8-THC by ketoconazole (id=NPDI-M13k5Q)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
4 . Inhibition of 11-hydroxylation of delta-8-THC by sulfaphenazole (id=NPDI-42-g8Q)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not available
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM
5 . Inhibition of 8-beta-hydroxylation of delta-9-THC by ketoconazole (id=NPDI-rbqhsA)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
6 . Inhibition of 11-hydroxylation of delta-9-THC by sulfaphenazole (id=NPDI-qmmKqA)
In Vitro Enzyme Inhibition Experiment
Inhibition was detected. Cutoff used —
Not provided
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM
7 . No Inhibition of 8-hydroxylation of cannabinol by 7,8-benzoflavone (id=NPDI-v8ghug)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
8 . Weak Inhibition of 11-hydroxylation of cannabinol by 7,8-benzoflavone (id=NPDI-YQ1c2Q)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
9 . Weak Inhibition of 11-hydroxylation of cannabinol by ketoconazole (id=NPDI-VpD-Xg)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
10 . Weak Inhibition of 8-hydroxylation of cannabinol by sulfaphenazole (id=NPDI-uxfWFg)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM
11 . Weak Inhibition of 11-hydroxylation of delta-8-THC by 7,8-benzoflavone (id=NPDI-RCBEtw)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
12 . No inhibition of 7-alpha-hydroxylation of delta-8-THC by 7,8-benzoflavone (id=NPDI-EYnQkA)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
13 . Weak Inhibition of 11-hydroxylation of delta-8-THC by ketoconazole (id=NPDI-M8-Oxw)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
14 . Weak Inhibition of 7-alpha-hydroxylation of delta-8-THC by sulfaphenazole (id=NPDI-5Fz7kg)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM
15 . No inhibition of 8-beta-hydroxylation of delta-9-THC by 7,8-benzoflavone (id=NPDI-THVK4A)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
16 . Weak Inhibition of 11-hydroxylation of delta-9-THC by 7,8-benzoflavone (id=NPDI-IQtjvw)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP1A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
17 . Weak Inhibition of 11-hydroxylation of delta-9-THC by ketoconazole (id=NPDI-abEayg)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP3A
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
10 µM
18 . Weak Inhibition of 8-beta-hydroxylation of delta-9-THC by sulfaphenazole (id=NPDI-Yr3jng)
In Vitro Enzyme Inhibition Experiment
Negligible Inhibition was detected. Cutoff used —
Not provided
- CYP2C
Cell fraction Pooled human liver microsomes -7999662
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
10 microG
Commercially available
20 min
NADPH
NADPH regenerating system
64 µM
50 µM