Inhibition of Rat CYP1A2 and CYP2C11 by Honokiol, a Component of Traditional Chinese Medicine
- 48 Downloads
Background and Objectives
Honokiol, a major constituent isolated from Magnolia officinalis, is regarded as a phytochemical marker and bioactive substance present in many traditional Chinese medicines. However, the effect of honokiol on cytochrome P450 (CYP) has not been thoroughly investigated. The aim of this study was to investigate the effect of honokiol on CYP1A2 and CYP2C11 in vitro and in vivo.
The effect of honokiol on CYP1A2 and CYP2C11 was investigated with rat liver microsomes (RLMs) by measuring phenacetin and tolbutamide metabolism (probe drugs for CYP1A2 and CYP2C11, respectively), and then explored in vivo by measuring the effect of honokiol (2.5 and 5 mg/kg, intravenous injection) on the pharmacokinetics of theophylline and tolbutamide (probe drugs for CYP1A2 and CYP2C11, respectively) in rats in vivo.
Honokiol inhibited the formation of acetaminophen from phenacetin and 4-hydroxytolbutamide from tolbutamide in RLMs, with inhibition constant (Ki) values of 1.6 μM and 16.5 μM, respectively. In vivo, honokiol (2.5 or 5.0 mg/kg) increased the half-life (t1/2) of theophylline by 40.9% and 119.9%, decreased the clearance (CL) by 23.8% and 42.9%, and increased the area under the curve (AUC) by 41.3% and 83.4%, respectively. Similarly, the t1/2 of tolbutamide increased by 25.5% and 33.8%, the CL decreased by 14.3% and 19.1%, and the AUC increased by 19.2% and 25.7%, respectively.
The inhibition of CYP1A2 by honokiol is greater than the inhibition of CYP2C11. The changes in the pharmacokinetics of theophylline and tolbutamide in rats treated with honokiol are due to the inhibition of CYP1A2 and CYP2C11 activity in a dose-dependent manner.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflict of interest.
This work was supported by Foundation for University Key Teacher by Henan province and Henan province Key Program of Science and Technology (Grant 162102310519). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The study was carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals, and the animal protocol was approved by the Medical Ethics Committee of Zhengzhou University.
- 6.Zhang QH, Gong C, Yang H, Wei H, Zhou WB, Qi C, et al. Pharmacokinetics of cisplatin in the absence or presence of zengmian yiliu granules (a traditional Chinese medicine compound) in rats determined via ICP-MS: an investigation on drug-herb interactions. Pharm Biol. 2015;53(2):159–66. https://doi.org/10.3109/13880209.2014.912241.CrossRefPubMedGoogle Scholar
- 7.Wang L, Wu C, Shen L, Liu H, Chen Y, Liu F, et al. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males. Xenobiotica. 2016;46(8):703–8. https://doi.org/10.3109/00498254.2015.1113576.CrossRefPubMedGoogle Scholar
- 12.Gao N, Zou D, Qiao HL. Concentration-dependent inhibitory effect of Baicalin on the plasma protein binding and metabolism of chlorzoxazone, a CYP2E1 probe substrate, in rats in vitro and in vivo. PLoS One. 2013;8(1):e53038. https://doi.org/10.1371/journal.pone.0053038.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Hahm ER, Arlotti JA, Marynowski SW, Singh SV. Honokiol, a constituent of oriental medicinal herb magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction. Clin Cancer Res. 2008;14(4):1248–57. https://doi.org/10.1158/1078-0432.CCR-07-1926.CrossRefPubMedGoogle Scholar
- 15.Sheng YL, Xu JH, Shi CH, Li W, Xu HY, Li N, et al. UPLC-MS/MS-ESI assay for simultaneous determination of magnolol and honokiol in rat plasma: application to pharmacokinetic study after administration emulsion of the isomer. J Ethnopharmacol. 2014;155(3):1568–74. https://doi.org/10.1016/j.jep.2014.07.052.CrossRefPubMedGoogle Scholar
- 17.Chao LK, Liao PC, Ho CL, Wang EI, Chuang CC, Chiu HW, et al. Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS-induced TNFalpha and NO expression. J Agric Food Chem. 2010;58(6):3472–8. https://doi.org/10.1021/jf904207m.CrossRefPubMedGoogle Scholar
- 18.Leeman-Neill RJ, Cai Q, Joyce SC, Thomas SM, Bhola NE, Neill DB, et al. Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. Clin Cancer Res. 2010;16(9):2571–9. https://doi.org/10.1158/1078-0432.CCR-10-0333.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos. 2003;31(7):815–32. https://doi.org/10.1124/dmd.31.7.815.CrossRefPubMedGoogle Scholar
- 27.Gao N, Fang Y, Qi B, Jia LJ, Jin H, Qiao HL. Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats. J Ethnopharmacol. 2013;150(2):477–84. https://doi.org/10.1016/j.jep.2013.08.062.CrossRefPubMedGoogle Scholar
- 30.Busby WF Jr, Ackermann JM, Crespi CL. Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Metabol Dispos. 1999;27(2):246–9.Google Scholar
- 31.Vertiz-Hernandez A, Castaneda-Hernandez G, Martinez-Cruz A, Cruz-Antonio L, Grijalva I, Guizar-Sahagun G. L-arginine reverses alterations in drug disposition induced by spinal cord injury by increasing hepatic blood flow. J Neurotrauma. 2007;24(12):1855–62. https://doi.org/10.1089/neu.2007.0375.CrossRefPubMedGoogle Scholar
- 34.Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S. Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression. Mol Endocrinol. 1989;3(9):1399–408. https://doi.org/10.1210/mend-3-9-1399.CrossRefPubMedGoogle Scholar
- 35.US FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available from: https://www.fda.gov/drugs/druginteractions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed 7 June 2019.
- 38.Kim SB, Kim KS, Ryu HM, Hong SH, Kim BK, Kim DD, et al. Modulation of rat hepatic CYP1A and 2C activity by honokiol and magnolol: differential effects on phenacetin and diclofenac pharmacokinetics in vivo. Molecules. 2018. https://doi.org/10.3390/molecules23061470.CrossRefPubMedPubMedCentralGoogle Scholar