Mechanism-based inhibition of Alantolactone on human cytochrome P450 3A4 in vitro and activity of hepatic cytochrome P450 in mice.

作者: Chong-Zhen Qin , Qiao-Li Lv , Na-Yiyuan Wu , Lin Cheng , Yun-Chen Chu

DOI: 10.1016/J.JEP.2015.03.061

关键词:

摘要: Abstract Ethnopharmacological relevance Alantolactone (AL), one of the main active ingredients in Inula helenium L. , has been included various prescriptions traditional Chinese medicine. The effects AL on cytochrome P450 (CYP450) were still unclear. This study evaluated inhibitory effect P450s vitro and vivo . Materials methods CYPs activity human liver microsomes (HLMs) recombinant cDNA-expressed enzymes incubation system, then determined by LC-MS/MS based probe substrate assay. C57BL/6 mice treated orally (0, 25, 50, 100 mg/kg) for 15 days. major Cyps examined at both mRNA enzyme levels. Results showed a potent CYP3A4 with IC 50 values 3.599 3.90 (recombinant CYP3A4) μM, respectively. strongly decreased dose-dependent but not time-dependent way HLMs. from typical Lineweaver–Burk plots that could inhibit noncompetitively, Ki value 1.09 μM Moreover, CYP2C19 also be inhibited 36.82 μM. Other CYP450 isoforms markedly affected AL. inhibition was validated mice. significantly expression Cyp2c 3a family. Conclusion indicates herb–drug interaction should paid more attention between drugs metabolized CYP3A4.

参考文章(29)
Chong-Zhen Qin, Xian Ren, Zhi-Rong Tan, Yao Chen, Ji-Ye Yin, Jing Yu, Jian Qu, Hong-Hao Zhou, Zhao-Qian Liu, A high-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography–tandem mass spectrometry Biomedical Chromatography. ,vol. 28, pp. 197- 203 ,(2014) , 10.1002/BMC.3003
Jason Lazarou, Bruce H. Pomeranz, Paul N. Corey, Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies JAMA. ,vol. 279, pp. 1200- 1205 ,(1998) , 10.1001/JAMA.279.15.1200
Xiu-Lan Xin, Xiao-Chi Ma, Ke-Xin Liu, Jian Han, Bao-Rong Wang, De-An Guo, Microbial transformation of alantolactone by Mucor polymorphosporus Journal of Asian Natural Products Research. ,vol. 10, pp. 933- 937 ,(2008) , 10.1080/10286020802240301
S Muruganandan, CJ Sinal, Mice as Clinically Relevant Models for the Study of Cytochrome P450-dependent Metabolism Clinical Pharmacology & Therapeutics. ,vol. 83, pp. 818- 828 ,(2008) , 10.1038/CLPT.2008.50
Soon Sung Lim, Ju Ryoung Kim, Hyun Ae Lim, Chan Ho Jang, Young Kyoon Kim, T Konishi, Eun Ji Kim, Jung Han Yoon Park, Jong-Sang Kim, None, Induction of Detoxifying Enzyme by Sesquiterpenes Present in Inula helenium Journal of Medicinal Food. ,vol. 10, pp. 503- 510 ,(2007) , 10.1089/JMF.2006.209
Muhammad Khan, Fei Yi, Azhar Rasul, Ting Li, Nan Wang, Hongwen Gao, Rong Gao, Tonghui Ma, Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction. Iubmb Life. ,vol. 64, pp. 783- 794 ,(2012) , 10.1002/IUB.1068
C. Lau, K.D. Mooiman, R.F. Maas-Bakker, J.H. Beijnen, J.H.M. Schellens, I. Meijerman, Effect of Chinese herbs on CYP3A4 activity and expression in vitro Journal of Ethnopharmacology. ,vol. 149, pp. 543- 549 ,(2013) , 10.1016/J.JEP.2013.07.014
R.X Tan, H.Q Tang, J Hu, B Shuai, Lignans and sesquiterpene lactones from Artemisia sieversiana and Inula racemosa Phytochemistry. ,vol. 49, pp. 157- 161 ,(1998) , 10.1016/S0031-9422(97)00889-3
Chun JaeMoo Chun JaeMoo, Choi RanJoo Choi RanJoo, S Khan, Lee DongSung Lee DongSung, Kim YounChul Kim YounChul, Nam YoungJoo Nam YoungJoo, Lee DongUng Lee DongUng, Kim YeongShik Kim YeongShik, Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. International Immunopharmacology. ,vol. 14, pp. 375- 383 ,(2012) , 10.1016/J.INTIMP.2012.08.011
Nicholas J. Lawrence, Alan T. McGown, Jane Nduka, John A. Hadfield, Robin G. Pritchard, Cytotoxic michael-type amine adducts of α-methylene lactones alantolactone and isoalantolactone Bioorganic & Medicinal Chemistry Letters. ,vol. 11, pp. 429- 431 ,(2001) , 10.1016/S0960-894X(00)00686-7