Evaluation of in vitro cytochrome P450 induction and inhibition activity of deoxyelephantopin,a sesquiterpene lactone from Elephantopus scaber L. |
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| Affiliation: | 1. Malaysian Institute of Pharmaceuticals & Nutraceuticals, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia;2. Pharmaceutical Design & Simulation (PhDS) Laboratory, Universiti Sains Malaysia, Pulau Pinang, Malaysia;3. Forest Research Institute Malaysia (FRIM), Selangor Darul Ehsan, Malaysia;4. School of Biological Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia;5. Advanced Medical & Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia;1. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box1982, Dammam 31441, Saudi Arabia;2. Malaysian Institute of Pharmaceuticals and Nutraceuticals, National Institutes of Biotechnology Malaysia, Halaman Bukit Gambir, 11700 Penang, Malaysia;3. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al Mauz, Nizwa 616, Sultanate of Oman;4. Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;5. Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan;6. Atta-ur-Rahman Institute for Natural Product Discovery, Aras 9 Bangunan FF3, UiTM Puncak Alam, 42300 Bandar, Baru Puncak Alam, Selangor, Malaysia;7. Faculty of Applied Science, UiTM Shah Alam, 40450 Shah Alam, Selangor D.E., Malaysia;8. Department of Chemistry, University of Wah, Quaid Avenue, Wah Cantt 47000, Pakistan;9. Department of Chemistry, University of Poonch, Rawalakot, AJK, Pakistan;10. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, 721013, China;2. Department of Medical Technology, Qiandongnan Vocational and Technical College for Nationalities, Kaili, 556000, China;3. Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases By TCM, Gansu Province, Lanzhou, 730000, China;4. School of Pharmacy and Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, China;1. Malaysian Institute of Pharmaceuticals and Nutraceuticals (IPharm), National Institutes of Biotechnology Malaysia, Ministry of Science, Technology and Innovation, Blok 5-A, Halaman Bukit Gambir, 11700 Penang, Malaysia;2. Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia;3. Centre for Drug Research (CDR), Universiti Sains Malaysia, 11800 Penang, Malaysia;4. Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia, 11800 Penang, Malaysia |
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| Abstract: | 
Drug metabolism involving cytochrome P450 (CYP) enzymes is a key determinant of significant drug interactions. Deoxyelephantopin was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4, and protein expression and resultant enzymatic activity. The mRNA and protein expression of cytochrome isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis, respectively. Human CYP3A4 protein expression was determined using an optimized hCYP3A4-HepG2 cell-based assay and the enzymatic activity was evaluated using P450-Glo™ CYP3A4 assay. The molecular interaction and possible inhibition of deoxyelephantopin of the CYP3A4 enzyme was determined in silico and further validated using substrate-specific CYP3A4 inhibition assays. Deoxyelephantopin produced no significant effect on the CYP1A2 and CYP2D6 mRNA and protein expression. However, it has a weak induction effect on CYP3A4 at the transcriptional level. In silico docking simulation showed that deoxyelephantopin has a weak interaction with CYP3A4 enzyme and it minimally affects the metabolism of CYP3A4 substrates. Deoxyelephantopin is not an in vitro CYP1A2 and CYP2D6 inducer. It is both a weak in vitro CYP3A4 inducer and inhibitor and is unlikely to elicit a clinically significant effect in human. |
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| Keywords: | Deoxyelephantopin CYP3A4 Cytochrome P450 induction assay Cytochrome P450 inhibition assay Drug–herb interactions |
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