In Vitro Investigation on the Effect of Dendrobine on the Activity of Cytochrome P450 Enzymes

Abstract

Dendrobine is the major active ingredient of Dendrobium nobile, Dendrobium chrysotoxum, and Dendrobium fimbriatum, all of which are used in traditional Chinese medicine owing to their antitumor and anti-inflammation activities. Hence, investigation on the interaction of dendrobine with cytochrome P450 enzymes could provide a reference for the clinical application of Dendrobium. The effects of dendrobine on cytochrome P450 enzymes activities were investigated in the presence of 0, 2.5, 5, 10, 25, 50, and 100 µM dendrobine in pooled human liver microsomes. The specific inhibitors were employed as the positive control and the blank groups were set as the negative control. The Lineweaver-Burk plots were plotted to characterize the specific inhibition model and obtain the kinetic parameters. The study reveals that dendrobine significantly inhibited the activity of CYP3A4, 2C19, and 2D6 with IC₅₀ values of 12.72, 10.84, and 15.47 µM, respectively. Moreover, the inhibition of CYP3A4 was found to be noncompetitive (Ki = 6.41 µM) and time dependent (KI = 2.541 µM⁻¹, K_inact  = 0.0452 min⁻¹), while the inhibition of CYP2C19 and 2D6 was found to be competitive with the Ki values of 5.22 and 7.78 µM, respectively, and showed no time-dependent trends. The in vitro inhibitory effect of dendrobine implies the potential drug-drug interaction between dendrobine and CYP3A4-, 2C9-, and 2D6-metabolized drugs. Nonetheless, these findings need further in vivo validation.

Key words

dendrobine - Dendrobium nobile - Dendrobium chrysotoxum - Dendrobium fimbriatum - CYP - metabolism - human liver microsomes - drug-drug interaction

Publication History

Received: 08 December 2021

Accepted after revision: 04 March 2022

Article published online:
06 May 2022

• References

• 1 Yang D, Cheng ZQ, Yang L, Hou B, Yang J, Li XN, Zi CT, Dong FW, Liu ZH, Zhou J, Ding ZT, Hu JM. Seco-dendrobine-type alkaloids and bioactive phenolics from Dendrobium findlayanum . J Nat Prod 2018; 81: 227-235
• 2 Zhang X, Wang M, Zhang C, Liu Z, Zhou S. Clinical study of Dendrobium Nobile Lindl intervention on patients with metabolic syndrome. Medicine (Baltimore) 2021; 100: e24574
• 3 Li R, Liu T, Liu M, Chen F, Liu S, Yang J. Anti-influenza a virus activity of dendrobine and its mechanism of action. J Agric Food Chem 2017; 65: 3665-3674
• 4 Feng Y, Jia B, Feng Q, Zhang Y, Chen Y, Meng J. Dendrobine attenuates gestational diabetes mellitus in mice by inhibiting Th17 cells. Basic Clin Pharmacol Toxicol 2021; 128: 379-385
• 5 Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: A review. Curr Drug Targets 2018; 19: 38-54
• 6 Chen Q, Yin C, Li Y, Yang Z, Tian Z. Pharmacokinetic interaction between peimine and paeoniflorin in rats and its potential mechanism. Pharm Biol 2021; 59: 129-133
• 7 Ci R, Zhang K, Zhu A, Zang W. Dendrobine attenuates isoniazid- and rifampicin-induced liver injury by inhibiting miR-295-5p. Hum Exp Toxicol 2020; 39: 1671-1680
• 8 Al-Ghamdi S, Aldossari K, Al-Zahrani J, Al-Shaalan F, Al-Sharif S, Al-Khurayji H, Al-Swayeh A. Prevalence, knowledge and attitudes toward herbal medication use by Saudi women in the central region during pregnancy, during labor and after delivery. BMC Complement Altern Med 2017; 17: 196
• 9 Mohammad Y, Al-Ahmari A, Al-Dashash F, Al-Hussain F, Al-Masnour F, Masoud A, Jradi H. Pattern of traditional medicine use by adult Saudi patients with neurological disorders. BMC Complement Altern Med 2015; 15: 102
• 10 Albassam AA, Ahad A, Alsultan A, Al-Jenoobi FI. Inhibition of cytochrome P450 enzymes by thymoquinone in human liver microsomes. Saudi Pharm J 2018; 26: 673-677
• 11 Li YY, Lyu CH, Wu G, Zheng ZB, Luo YB, Qin S. Research progress on molecular mechanism of Dendrobium officinale and its active components to metabolic syndrome. Zhongguo Zhong Yao Za Zhi 2019; 44: 5102-5108
• 12 Guengerich FP. Cytochrome P450 research and The Journal of Biological Chemistry . J Biol Chem 2019; 294: 1671-1680
• 13 Tian D, Hu Z. CYP3A4-mediated pharmacokinetic interactions in cancer therapy. Curr Drug Metab 2014; 15: 808-817
• 14 Li Y, Ning J, Wang Y, Wang C, Sun C, Huo X, Yu Z, Feng L, Zhang B, Tian X, Ma X. Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects. Toxicol Lett 2018; 294: 27-36
• 15 Meng M, Li X, Zhang X, Sun B. Baicalein inhibits the pharmacokinetics of simvastatin in rats via regulating the activity of CYP3A4. Pharm Biol 2021; 59: 880-883
• 16 Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017; 13: 323-330
• 17 Depta JP, Lenzini PA, Lanfear DE, Wang TY, Spertus JA, Bach RG, Cresci S. Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J 2015; 15: 20-25
• 18 Lessard E, Yessine MA, Hamelin BA, OʼHara G, LeBlanc J, Turgeon J. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 1999; 9: 435-443
• 19 Bahar MA, Setiawan D, Hak E, Wilffert B. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics 2017; 18: 701-739
• 20 Riley RJ, Grime K, Weaver R. Time-dependent CYP inhibition. Expert Opin Drug Metab Toxicol 2007; 3: 51-66
• 21 Wang S, Wu H, Geng P, Lin Y, Liu Z, Zhang L, Ma J, Zhou Y, Wang X, Wen C. Pharmacokinetic study of dendrobine in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry. Biomed Chromatogr 2016; 30: 1145-1149
• 22 Pan H, Shi FG, Fang C, Shi JS. Metabolic characterization of a potent natural neuroprotective agent dendrobine in vitro and in rats. Acta Pharmacol Sin 2021; 43: 1059-1071
• 23 Huang CL, Fan XM, Li Q, Wang YM, Wang SM, Gong MJ, Luo GA. Effect of processed Polygonum multiflorum on mRNA expression level of five subtypes of CYP450 enzymes in rat liver. Zhongguo Zhong Yao Za Zhi 2017; 42: 352-356
• 24 Michaud V, Frappier M, Dumas MC, Turgeon J. Metabolic activity and mRNA levels of human cardiac CYP450s involved in drug metabolism. PLoS One 2010; 5: e15666
• 25 Wang J, Zhai T, Chen Y. Effects of honokiol on CYP450 activity and transporter mRNA expression in type 2 diabetic rats. Int J Mol Sci 2018; 19: 815
• 26 Li Y, Qin J, Wu H, Xu Y, Zhang L, Su K, Cui Y, Wang H. In vitro inhibitory effect of lysionotin on the activity of cytochrome P450 enzymes. Pharm Biol 2020; 58: 695-700
• 27 Zhang N, Liu J, Chen Z, Dou W. In vitro inhibitory effects of kaempferitrin on human liver cytochrome P450 enzymes. Pharm Biol 2019; 57: 571-576
• 28 Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS. Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem 2012; 55: 4896-4933