Investigation on P450s involved in emodin's phaseⅠmetabolism and inhibitory effect of emodin on P450s

Abstract

Abstract: AIM: To identify the P450s involved in emodin's phaseⅠmetabolism and inhibitory effect of emodin on the P450s, in order to provide experimental evidence for predicting possible emodin-drug interactions.METHODS: Human liver microsome and recombinant P450 enzymes were incubated with emodin and CYP3A4 inhibitor ketoconazole (KTZ) for 20 mins in vitro, emodin concentrations were determined by LC-MS/MS method. Inhibitory effects of emodin on the P450 enzyme isoforms were investigated using an established in vitro cocktail incubation approach in our lab.RESULTS: Co-incubation with human liver microsomes and recombinant CYP3A4 system in vitro showed that emodin remains 68.5% and 0.015% of the initial content, 100 μmol/L KTZ could decrease the elimination rate to 0.1% and 27.7% respectively. The results from the cocktail experiment indicated that emodin had a moderate inhibition on CYP1A2, CYP2C9, CYP2D6 with IC₅₀ as 3.31, 2.60, 2.56 μmol/L respectively.CONCLUSION: CYP3A4 plays a key role for emodin biotransformation in phaseⅠmetabolism, possessing the inhibitory effect on multiple P450s. Attention should be paid to avoid the possible emodin-drug interaction when emodin-containing preparations are prescribed with substrates of these mentioned P450s.

Key words: drug interactions, emodin, metabolic enzyme, pregnane X receptor, inhibitor

CLC Number:

R965.2

WANG Lai-you, LI Jing-qing, CHEN Tao, TANG Qian-jie, CHEN Ling-yan. Investigation on P450s involved in emodin's phaseⅠmetabolism and inhibitory effect of emodin on P450s[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(3): 241-245.

References

[1] 刘晗, 高云.大黄素药理作用的分子机制的研究进展[J]. 中国药理学通报,2009, 25(12): 1552-1555.
[2] 吴艳霞,付雷,黄浩.大黄素对心肌梗死后小鼠心肌组织TNF-α、IL-10基因表达和NF-κB活性的影响[J]. 中国临床药理学与治疗学,2010, 15(3): 287-291.
[3] Li D, Zhang N, Cao Y, et al. Emodin ameliorates lipopolysaccharide-induced mastitis in mice by inhibiting activation of NF-κB and MAPKs signal pathways[J]. Eur J Pharmacol, 2013, 705(1/2/3):79-85.
[4] Badria FA, Ibrahim AS. Evaluation of natural anthracene-derived compounds as antimitotic agents[J]. Drug Discov Ther, 2013, 7(2):84-89.
[5] Oshida K, Hirakata M, Maeda A, et al. Toxicological effect of emodin in mouse testicular gene expression profile[J]. J Appl Toxicol, 2011, 31(8):790-800.
[6] Chang MH, Huang FJ, Chan WH. Emodin induces embryonic toxicity in mouse blastocysts through apoptosis[J]. Toxicology, 2012, 299(1):25-32.
[7] He Q, Liu K, Wang S, et al. Toxicity induced by emodin on zebrafish embryos[J]. Drug Chem Toxicol,2012, 35(2):149-154.
[8] Shia CS, Tsai SY, Lin JC, et al. Steady-state pharmacokinetics and tissue distribution of anthraquinones of Rhei Rhizoma in rats[J]. J Ethnopharmacol, 2011, 137(3):1388-1394.
[9] Zhang L, Ma WF, Li J, et al. Influence of processing on pharmacokinetic of typical constituents in radix polygoni multiflori after oral administration by LC-ESI-MS/MS[J]. J Ethnopharmacol, 2013, 148(1):246-253.
[10] Han XH, Zhong J, Guo JY, et al. Relationships between pharmacokinetics and efficacy of Xie-xin decoction in rats with experimental ulcerative colitis[J]. J Ethnopharmacol, 2013, 148(1):182-189.
[11] 周方,许红梅.大黄素对肝内胆汁淤积大鼠P-gp表达的影响[J].中国中药杂志,2010, 35(7):908-911.
[12] Liu YH, Mo SL, Bi HC, et al. Regulation of human pregnane X receptor and its target gene cytochrome P450 3A4 by Chinese herbal compounds and a molecular docking study[J]. Xenobiotica, 2011, 41(4):259-280.
[13] Li F, Wang L, Guo GL, et al. Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice[J]. Drug Metab Dispos, 2010, 38(5):871-878.
[14] 和凡,黄民. 细胞色素P450酶活性评价的体外“cocktail”高通量筛选模型的建立和应用[D].中山大学临床药理研究所博士学位论文, 2007.
[15] 刘柏东,黄芝瑛,黄民. CYP450酶活性评价的“cocktai”模型的优化与应用[D].中山大学临床药理研究所硕士学位论文, 2009.
[16] 王青秀,廖明阳,吴纯启.大黄及其主要成分的毒性毒理研究[D].中国人民解放军军事医学研究院毒物药物研究所博士学位论文, 2007.
[17] 赵其锦,查伟斌,周芳,等.孕烷X受体介导的代谢酶和转运体转录调控及其在化疗药物耐药中的作用[J].中国临床药理学与治疗学, 2012, 17(8): 931-940.