Effects of Green Tea Catechins on Cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A Activities in Human Liver and Intestinal Microsomes
Effects of Green Tea Catechins on Cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A Activities in Human Liver and Intestinal Microsomes
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DOI：
10.2133/dmpk.dmpk-12-rg-101
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发表时间：
2013-06-25
影响因子：
2.1
通讯作者：
Yamada, Shizuo
中科院分区：
文献类型：
--
作者：
Misaka, Shingen;Kawabe, Keisuke;Yamada, Shizuo
绿色茶儿茶素对主要药物代谢酶系统细胞色素P450（CYP）的影响尚未完全阐明。本研究的目的是评价绿色茶提取物（GTE，总儿茶素86.5%，w/w）和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）对CYP 2B 6，CYP 2C 8，CYP 2C 19，CYP 2D 6和CYP 3A活性的影响。在存在或不存在不同浓度的GTE和EGCG的情况下，评估安非他酮羟基化、阿莫地喹N-脱乙基化、（S）-美芬妥英4 '-羟基化、美沙芬O-脱甲基化和咪达唑仑1'-羟基化，以分别检测其对CYP 2B 6、CYP 2C 8、CYP 2C 19、CYP 2D 6和CYP 3A活性的影响。使用UPLC/ESI-MS定量每种代谢物，并分析GTE和EGCG对β-内酰胺酶的抑制动力学。在人肝微粒体中，GTE对CYP 2B 6、CYP 2C 8、CYP 2C 19、CYP 2D 6和CYP 3A的IC 50值分别为5.9、4.5、48.7、25.1和13.8 μ g/mL。ECGC也能抑制这些CYP 2B 6和CYP 2C 8亚型，并对CYP 3A产生非竞争性抑制。在人肠微粒体中，GTE和EGCG对CYP 3A的IC 50值分别为18.4 μ g/mL和31.1 μ M。EGCG以非竞争性方式中度抑制CYP 3A活性。这些结果表明，绿色茶儿茶素与CYP 2B 6和CYP 2C 8底物以及CYP 3A底物产生临床相关的相互作用。
The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 mu g/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 mu g/mL and 31.1 mu M, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.