Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions
Abstract
:1. Introduction
2. Results
2.1. Inhibition of CYP Activity by Aqueous Extract of Dried Aerial Plant Material
2.2. Inhibition of CYP1A2 Activity by Different Crude Extracts of H. verticillata (Aerial Plant)
2.3. Antioxidant Assays
2.4. Standardization of Dried Aerial Plant Aqueous Extract by RP-HPLC and LC-MS
2.4.1. RP-HPLC
2.4.2. LC-MS
2.5. Inhibition of CYP1A2 Activity by Key Phytochemicals Present in H. verticillata
2.5.1. Key Phytochemicals—Mixed Lignans, (-)-Yatein and β-Sitosterol
2.5.2. Key Phytochemicals—Oleanolic and Ursolic acid, Cadina-4,10(15)-Dien-3-One, Podophyllotoxin, 4′-Demethylpodophyllotoxin and Rosmarinic Acid
2.5.3. Inhibition of CYP1A2 Activity—Summary
3. Discussion
4. Material and Methods
4.1. Reagents
4.2. Co-Expressed Human CYP Enzymes
4.3. Preparation of Crude Plant Extracts
4.3.1. Aqueous Extracts—Dried Plant (Leaf and Stem)
4.3.2. Aqueous Extracts—Fresh Plant (Leaf and Stem)
4.3.3. Ethanol Extracts—Dried and Fresh Plant (Leaf and Stem)
4.4. Standardization of Dried Plant Aqueous Extract (Leaf and Stem) by Reversed Phase HPLC (RP-HPLC) and LC-MS
4.4.1. High Performance Liquid Chromatography (HPLC)
4.4.2. Liquid Chromatography—Mass Spectrometry (LC-MS)
4.5. In Vitro Inhibition of CYP Activity
4.6. Controls Assessment
4.6.1. Positive Control Inhibition for CYP450 Assays (CYPs 1A1, 1A2, 1B1, 2D6, 3A4)
4.6.2. Solvent Impact on CYP1A2 Activity
4.6.3. Intrinsic Fluorescence
4.6.4. Metabolite Fluorescence Quenching
4.7. Antioxidant Assay
4.8. Data Analysis
4.8.1. Measuring Cytochrome P450 Inhibition
4.8.2. Antioxidant Assay
Acknowledgments
Author Contributions
Conflicts of Interest
Appendix A
Appendix B
Phytochemicals Identified in H. verticillata (Published and Unpublished) | RP-HPLC Standard | Empirical Formula | m/z—Calculated Value 1 (Difference Between m/z Value and Mono-Isotopic Mass Where the Difference is ≤1.0) | |||||
---|---|---|---|---|---|---|---|---|
[M + H] + | [M + CH3] + | [M + H2O] + | [M + Na] + | [M + CH3OH] + | [M + K] + | |||
Cadina-4,10(15)-dien-3-one | (−) | C15H22O | ||||||
Cadina-10(15)-en-3-one | C15H22O | |||||||
Aromadendr-1(10)-en-9-one | C15H22O | |||||||
7,11,15-Trimethyl-3-methylenehexadecane -1,2-diol | C20H40O2 | 330.3 (0.9) | ||||||
Rosmarinic acid | C18H16O8 | 392.3 (0.97) | ||||||
Deoxydehydropodophyllotoxin 2 | (+) | C22H18O7 | 409.1 (0.1) | 433.1 (0.7) | ||||
Dehydrodesoxypodophyllotoxin | C22H18O7 | 409.1 (0.1) | 433.1 (0.7) | |||||
ß-Apopicropodophyllin | C22H20O7 | 419.0 (0.4) | ||||||
Hyptinin | C22H20O7 | 419.0 (0.4) | ||||||
Isodeoxypodophyllotoxin | C22H22O7 | 437.1 (0.2) | ||||||
Deoxypicropodophyllin | C22H22O7 | 437.1 (0.2) | ||||||
4-Demethylpodophyllotoxin | (+) | C21H20O8 | 418.1 (0.3) | 432.1 (0.3) | ||||
(-)-Yatein | (+) | C21H20O8 | 418.2 (0.2) | 432.2 (0.2) | ||||
Dehydropodophyllotoxin 2 | (+) | C22H18O8 | 433.0 (0.6) | |||||
Podophyllotoxin | (+) | C22H22O8 | 432.1 (0.3) | 437.0 (0.3) | ||||
ß-Peltatin | C22H22O8 | 432.1 (0.3) | 437.0 (0.3) | |||||
ß -Sitosterol 3 | (−) | C29H50O | 432.4 (0.0) | 437.3 (0.0) | ||||
Oleanolic acid 4 | (+) | C30H48O3 |
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Sample Availability: Not available. |
Phytochemicals Identified in H. verticillata by LC-MS | Empirical Formula | Mono-isotopic Mass (Da) 1 | Confirmation by RP-HPLC Standard |
---|---|---|---|
Cadina-10(15)-en-3-one | C15H22O | 218.167 | |
Aromadendr-1(10)-en-9-one | C15H22O | 218.167 | |
7,11,15-Trimethyl-3-methylenehexadecane -1,2-diol | C20H40O2 | 312.303 | |
Rosmarinic acid | C18H16O8 | 360.315 | |
Deoxydehydropodophyllotoxin 2 | C22H18O7 | 394.105 | (+) |
Dehydrodesoxypodophyllotoxin | C22H18O7 | 394.105 | |
ß-Apopicropodophyllin | C22H20O7 | 396.121 | |
Hyptinin | C22H20O7 | 396.121 | |
Isodeoxypodophyllotoxin | C22H22O7 | 398.136 | |
Deoxypicropodophyllin | C22H22O7 | 398.136 | |
4-Demethylpodophyllotoxin | C21H20O8 | 400.116 | (+) |
(-)-Yatein | C21H20O8 | 400.152 | (+) |
Dehydropodophyllotoxin 2 | C22H18O8 | 410.100 | (+) |
Podophyllotoxin | C22H22O8 | 414.131 | (+) |
ß-Peltatin | C22H22O8 | 414.131 | |
Oleanolic acid 3 | C30H48O3 | 456.360 | (+) |
Test Phytochemical | Concentration Range Tested [µg/mL] | Solvent (Highest % v/v) | IC50 (µg/mL) |
H. verticillata aqueous extract (dried aerial material) | 0.25–60 | H2O | 1.9 ± 0.5 |
Lignan Mix | 0.08–180 | DMF (2.0) | 61.8 ± 0.7 |
-Dehydropodophyllotoxin -Deoxydehydropodophyllotoxin -4′-Demethyldesoxypodophyllotoxin -5′-Methoxydehydropodophyllotoxin -Dehydro-β-peltatin methyl ether | |||
Test Phytochemical | Concentration Range Tested [µM] | Solvent (Highest % v/v) | IC50 (μM) |
Podophyllotoxin | 2.9–369 | DMF (0.7) | No inhibition |
4′-Demethylpodophyllotoxin | 0.28–611 | DMF (0.7) | No inhibition |
(-)-Yatein | 0.18–400 | DMF (1.2) | 71.9 ± 1.8 |
Cadina-4,10(15)-dien-3-one | 0.28–623 | H2O | >500 |
Oleanolic acid | 0.9–219 | DMF (1.3) | >100 |
Ursolic acid | 0.05–117 | DMF (1.8) | >100 |
β-Sitosterol | 5.1–410 | DMF (2.0) | 160 ± 3.4 |
Furafylline—reference inhibitor | 0.04–96 | 1.4 ± 0.15 |
Phytochemicals | Reported CYP Inhibition | IC50 Value (μM) | Reference |
---|---|---|---|
Podophyllotoxin | CYP3A4 | Potent inhibitor (IC50 not stated) | [40] |
Dehydropodophyllotoxin | None | - | |
Deoxydehydropodophyllotoxin | None | - | |
4′-Demethyldesoxypodophyllotoxin | None | - | |
4′-Demethylpodophyllotoxin | None | - | |
5′-Methoxydehydropodophyllotoxin | None | - | |
Dehydro-β-peltatin methyl ether | None | - | |
(-)-yatein | CYP3A4 CYP2D6 | 1.095.7 | [39] [39] |
Oleanolic acid | CYP1A2 CYP2C8/C9/C19 CYP3A4 CYP2D6 | 143.5 >500 78.9 >500 | [38] [38] [38] [38] |
Ursolic acid | CYP1A2 CYP2C8/C9/C19 CYP3A4 CYP2D6 | 352.4 >500 >500 438.9 | [38] [38] [38] [38] |
Rosmarinic acid | CYP2C9 CYP2D6 CYP3A4 CYP3A4 | 318.9 >500 241.2 No impact | [49] [49] [49] [50] |
ß-Sitosterol | CYP2D6 CYP3A4 CYP3A4/3A5 CYP2C19 | >100 >100 No impact No impact | [51] [51] [52] [52] |
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Picking, D.; Chambers, B.; Barker, J.; Shah, I.; Porter, R.; Naughton, D.P.; Delgoda, R. Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions. Molecules 2018, 23, 430. https://doi.org/10.3390/molecules23020430
Picking D, Chambers B, Barker J, Shah I, Porter R, Naughton DP, Delgoda R. Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions. Molecules. 2018; 23(2):430. https://doi.org/10.3390/molecules23020430
Chicago/Turabian StylePicking, David, Bentley Chambers, James Barker, Iltaf Shah, Roy Porter, Declan P Naughton, and Rupika Delgoda. 2018. "Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions" Molecules 23, no. 2: 430. https://doi.org/10.3390/molecules23020430