人UGTIA3催化黄酮类化合物葡醛酸结合反应定量构效关系研究

目的建立人UGTlA3催化黄酮类化合物定量构效关系，考察不同结构参数对葡醛酸结合反应的影响。方法采用半经验量子化学计算法MOPAC-AMl及逐步回归方法对11个黄酮类化合物的结构参数和UGTlA3催化葡醛酸反应的K。值进行定量构效关系研究。结果所建立的QSMR模型（pKm=-2．20707＋0．00256HOF＋3、21290Qc5）具有较好的拟合性。结论分子生成热（HOF）和5位C上的静电荷这两个结构参数是影响其葡醛酸结合活性的主要结构因素。     

卡维地洛与一些常用化学药的体外葡醛酸化代谢性相互作用

 目的研究卡维地洛与一些常用化学药的葡醛酸化代谢性相互作用,为临床合理用药提供科学依据。方法选择42种临床上可能合用的药物与卡维地洛在鼠肝微粒体中共孵育。以HPLC测定孵育液中卡维地洛葡醛酸结合物的浓度,计算共孵育药物对卡维地洛2个葡醛酸结合物的IC₅₀或K_i值。结果非洛地平,拉西地平,尼群地平,辛伐他汀和洛伐他汀对卡维地洛葡醛酸化代谢均有较强的体外抑制作用,Ki值在0.65～63.48μmol·L^-1之间。这5种药物对卡维地洛葡醛酸结合物M1的K_i值均低于对M2的K_i值,对M1的抑制作用强于对M2的抑制作用。其中拉西地平对M1和M2的抑制作用最强,K_i值分别约0.65和6.44μmol·L^-1。结论这5种药物对卡维地洛葡醛酸化代谢有较强的体外抑制作用,在联合用药时应引起注意。     

天然黄酮类化合物对大鼠心肌细胞抗凋亡作用的微观机制及构效关系研究

 目的 建立黄酮类化合物对大鼠心肌细胞抗凋亡率的定量构效关系模型,探讨其抗凋亡作用的微观机制。方法 采用半经验量子化学计算法MOPAC-AM1计算黄酮类化合物的量化参数,运用最佳变量子集回归及人工神经网络BP算法建立黄酮类化合物抗凋亡率的QSAR模型。结果 最佳二元线性回归模型的交叉验证系数（r 2_CV）为0.707,非交叉验证的相关系数(r)为0.928;相应BP-QSAR模型的r为0.996,估计标准误差(S)为0.013。结论 羟基指数(L)与碳电荷(Q_C)揭示了影响黄酮类化合物抗凋亡率的本质因素;其中,A、C环上羟基对自由基的链传递起主要阻断作用。
     

普萘洛尔对映体人体葡醛酸化立体选择性代谢研究

 目的 测定健康志愿者口服一定量消旋普萘洛尔后尿中两种不同构型普萘洛尔葡醛酸苷的排泄量，研究普萘洛尔对映体人体葡醛酸化代谢的立体选择性。方法 用生物合成法合成R-（+）-普萘洛尔葡醛酸苷，并经C₁₈固相萃取柱纯化、浓集，得到标准储备液，用于尿中普萘洛尔葡醛苷含量测定，计算药动学参数。结果 R-(+)-普萘洛尔葡醛酸苷与S(-)-普萘洛尔葡醛酸苷的消除速率常数（K）分别为(0.283?3±0.058)与(0.194?6±0.040)h^-1，达峰时(t_max)分别为(1.75±0.33)与(2.21±0.45)h，24 h累积尿药量（X_u）分别为(2.952±0.615)与(5.648±0.977)μmol。结论 人体葡萄糖醛酸转移酶对普萘洛尔光学异构体葡醛酸结合反应的催化作用有立体选择性。     

大黄素-大黄素甲醚型二蒽酮化合物安全性研究

目的 评价大黄素-大黄素甲醚型二蒽酮化合物的潜在肝毒性风险。方法 采用计算机分子对接构建尿苷二磷酸-葡萄糖醛酸转移酶1A1（UGT1A1）与反式-大黄素-大黄素甲醚二蒽酮（trans-EPD）、顺式-大黄素-大黄素甲醚二蒽酮（cis-EPD）的结合模型,考察化合物与酶蛋白的结合位点及结合强弱;体外采用大鼠肝微粒体酶抑制实验评价化合物对UGT1A1的抑制作用;通过细胞增殖与活性检测试剂盒-8（CCK-8）评价化合物对肝细胞活力的影响;采用荧光定量聚合酶链式反应（qRT-PCR）实验检测肝细胞中UGT1A1 mRNA水平。结果 计算机分子对接实验结果显示,trans-EPD及cis-EPD均与UGT1A1结合于site F区;体外酶抑制实验及细胞毒性实验证明,trans-EPD和cis-EPD均可显著抑制UGT1A1活性,下调其基因表达,产生肝细胞毒性作用。结论 具有大黄素（10→10′）大黄素甲醚或大黄素（10→10′）大黄素甲醚母核结构的二蒽酮化合物可能是一类具有潜在肝毒性的化合物,其作用靶点为胆红素代谢酶UGT1A1。研究结果为此类成分的临床安全用药提供参考。     

5种黄连生物碱大鼠体外肝代谢特征比较

目的 探讨黄连中5种结构相似异喹啉生物碱大鼠体外肝代谢的选择性。方法 采用大鼠体外肝微粒体温孵方法,通过考察温孵时间、微粒体蛋白浓度以及底物浓度对小檗碱、巴马汀、黄连碱、表小檗碱和药根碱代谢的影响,求得代谢反应动力学参数K_m、V_max和CL_int。结果 5种黄连生物碱成分的体外肝代谢动力学参数K_m和CL_int间差异明显（P＜0.05）。结论 黄连中5种异喹啉生物碱大鼠体外肝代谢存在显著选择性。     

健康人UGT1A9基因多态性与麦考酚酸药动学的关系

 目的探讨中国健康人麦考酚酸(MPA)药动学特性与尿苷二磷酸葡醛酸转移酶UGT1A9基因多态性的关系。方法采集20名健康男性单次po 500 mg麦考酚酸酯后48 h内不同时间点的血样。HPLC测定麦考酚酸(MPA)和葡醛酸化麦考酚酸(MPAG)的药物浓度。UGT1A9的基因多态性采用测序法测定,包括-2208,-2152,-2141,-1887,-1818,-665,-440,-331,-275,-109至-98(Tn),-87 11个位点。结果20名受试者中,-2208,-2152,-2141,-665,-275位点未发现突变,-440和-331位点均为纯合突变型,-1887,-1818,-109至-98(Tn)和-87的突变率分别为0.25,0.7,0.75,0.05。统计学检验未发现MPA和MPAG的ρ_max,AUC_0-t以及二者的比值与上述单核苷酸多态性有显著性差异。结论中国人群UGT1A9的基因多态性与白种人存在差异,且未发现UGT1A9的基因多态性与MPA的药动学特征有关。     

中国肝移植受者口服环孢素的临床常规监测群体药动学研究

 目的 考察肝移植受者口服环孢素的群体药动学特征,为实施个体化用药提供新途径。方法 回顾性收集120例肝移植病人全血稳态谷浓度样本1 947个,利用NONMEM软件考察一天给药剂量,分析其群体药动学模型,估算参数、个体间变异（interindividual variability, IIV）、时间效应变异（interoccasion variability, IOV）和个体内变异,定量考察人口统计学资料、生理状态、肝肾功能和合并用药等因素对药物药动学参数的影响,建立最终回归模型,应用POSTHOC子模块反馈获得个体和群体的药动学参数及预测给药剂量。模型验证用近似外部验证和bootstrap内部验证法。结果 环孢素稳态浓度能用米曼氏模型较好的拟合,最终群体药动学参数Vm为303 mg·d-1,K_m为14.90 μg·L-1。Vm和K_m的IIV分别为12.60%和89.78%,IOV分别为12.30%和36.88%,残差变异为4.00%。 Vm结构模型参数有用药天数（DT）、红细胞压积（HCT）、总蛋白（TP）、尿素（BUN）、甘油三酯（TG）、吗替麦考酚酸酯剂量（MMF）。K_m结构模型参数有胆红质（DBIL）和泼尼松剂量（PR）。结论 NONMEM法考察临床常规监测数据应当考虑IOV,分析得到的群体药动学模型可为临床患者提供用药依据。     

喜树碱及其衍生物结构修饰及构效关系的研究

 目的对喜树碱及其衍生物的结构修饰及构效关系进行研究。方法查阅国外最新文献,进行分析、归纳和总结。结果A,B,C和D环的平面共轭结构及C₂₀的S构型是喜树碱类化合物体内外活性所必需的;E环内酯部分的作用有待重新评价;在20(S)-羟基和喹啉环(A/B环)上引入功能基团作为结合位点的喜树碱结合物有利于提高喜树碱的作用效果。结论喜树碱新构效关系的阐明为喜树碱药物的合成提供了新的思路。     

龙葵碱对HepG2细胞NAT1酶活性及动力学影响的研究

 目的 探讨龙葵碱诱导HepG2细胞凋亡的芳香胺N-乙酰化转移酶（NAT1的影响。方法 采用高效液相色谱法(HPLC,以对氨基苯甲酸(PABA为底物,以PABA被NAT1乙酰化为乙酰对氨基苯甲酸(Ac-PABA的量反应NAT1酶的活性。观察不同浓度、不同时间龙葵碱对完整HepG2细胞NAT1酶活性的影响;龙葵碱对HepG2细胞细胞质中NAT1酶活性的影响;通过改变底物PABA浓度,采用双倒数作图法,以底物PABA浓度的倒数(1/S对NAT1反应速率的倒数(1/V作直线,得出回归方程,计算K_m和V_max。结果 在NAT1酶活性测定中,龙葵碱能显著降低HepG2完整细胞NAT1的活性;龙葵碱能够降低HepG2细胞质内NAT1的活性;随着作用时间的增加Ac-PABA生成的量逐渐增加,但在相同作用时间段龙葵碱能显著降低Ac-PABA生成的量。动力学研究表明,以PABA为底物,对于HepG2完整细胞,阴性对照组的K_m和V_max分别为(1.04×10-3±8.36×10-5mmol·L -1、(1.64×10-4±9.57×10-6 nmol·106 cells-1,龙葵碱组的K_m和V_max分别为(1.06×10-3±6.97×10-5 mmol·L-1和(1.48×10-4±4.28×10-6 nmol·106 cells-1·h-1。对于HepG2细胞质,阴性对照组的K_m和V_max分别为(3.32×10-1±2.35×10-4mmol·L -1、(2.60×10-3±6.79×10-6 nmol·h-1·mg pro-1,龙葵碱组的K_m和V_max分别为(3.35×10-1±1.66×10-4 mmol·L-1和(2.22×10-3±8.12×10-6 nmol·h-1·mg（Pro-1,经统计学处理表明,对于HepG2完整细胞和细胞质,阴性对照组和龙葵碱组的K_m没有差异,而V_max差异显著。结论 龙葵碱是HepG2细胞NAT1酶的非竞争性抑制剂。龙葵碱通过作用于NAT1与PABA结合位点以外的其他位点抑制NAT1酶的活性而诱导HepG2细胞凋亡。     

UGT88B2: A promiscuous O-glycosyltransferase from Carthamus tinctorius

Objective: In order to obtain new glycosyltransferases with highly efficient catalysis, the glycosyltransferases from Carthamus tinctorius which contains diverse types of glycosides were mined. Methods: A new glycosyltransferase gene (UGT88B2) with full length was obtained by PCR and further transformed into Escherichia coli for heterologous expression. The catalytic activity of recombinant UGT88B2 was determined by HPLC-MSn. The structures of representative catalytic products were elucidated by MS and NMR. Results: UGT88B2 exhibited catalytic promiscuity and various patterns in glycosylation of flavonoids with high efficiency. Conclusion: A new glycosyltransferase named UGT88B2 was successfully mined and can be employed as enzymatic tools in glycosylation of flavonoids.     

聚乙二醇400对黄芩苷及其主代谢物胆汁排泄的影响

目的:考察药用辅料聚乙二醇400(PEG400)对黄芩苷及其主代谢物黄芩素6-O-β-D-葡萄糖醛酸苷(B6G)胆汁排泄的影响,并分析其作用机制。方法:大鼠随机分为黄芩苷+水组与黄芩苷+PEG400组,利用10%水合氯醛(剂量4 mL·kg-1)腹腔注射诱导麻醉,制作大鼠胆管插管模型,待大鼠完全清醒后,以168 mg·kg-1剂量的黄芩苷分别给大鼠灌胃相应的黄芩苷水溶液和黄芩苷PEG400溶液,收集给药后0~12 h的胆汁,使用UPLC-MS/MS测定不同时间段药物经胆汁排泄的浓度,采用Thermo Hypersil GOLD C18色谱柱(2.1 mm×100 mm,1.9μm),流动相乙腈(A)-0.1%甲酸水溶液(B)梯度洗脱(0~9 min,90%~27%B;9~10 min,27%~90%B;10~12 min,90%B),流速0.3 mL·min^-1,柱温30℃,进样量5μL;质谱条件为电喷雾离子源(ESI),正离子检测模式。利用体外孵育法和酶联免疫吸附测定(ELISA)研究PEG400对尿苷二磷酸葡萄糖醛酸转移酶(UGT)1A8和UGT1A9活性及二者在大鼠肝脏中表达的影响。结果:与黄芩苷+水组相比,黄芩苷+PEG400组大鼠12 h内胆汁中黄芩苷及其主代谢物B6G的累积排泄量分别增加了1.8,2.1倍;PEG400分别使UGT1A8与UGT1A9的酶活性提高了2.0,1.5倍,使肝脏中UGT1A8与UGT1A9的质量分数提高了2.2,1.3倍。结论:PEG400可通过提高UGT1A8与UGT1A9的活性和表达来显著增加黄芩苷及其主代谢物B6G的胆汁排泄,且对B6G胆汁排泄的促进作用大于原形药物黄芩苷,可为PEG400的临床合理应用及黄芩苷等黄酮类药物新剂型的设计提供依据。     

人孕烷X受体介导的UGT1A1报告基因模型的建立及初步应用

 目的 建立基于人孕烷X受体（human pregnane X receptor,hPXR）的UGT1A1的报告基因模型,研究中药提取物通过人孕烷X受体途径对UGT1A1的潜在诱导能力。方法 以人基因组DNA为模板扩增UGT1A1的远端和近端启动子,连接到pGL3载体上,构建pGL3-PXRE重组质粒,并与人孕烷X受体表达质粒共转染HepG2细胞,从而建立报告基因模型。运用该模型考察了9种常见中药对人孕烷X受体的激活作用,即对UGT1A1的潜在诱导作用。结果 将UGT1A1启动子片段克隆到pGL3载体上,构建了pGL3-PXRE重组质粒,成功构建了报告基因模型,并考察了多种常见中药的提取物通过人孕烷X受体途径对UGT1A1的诱导作用。结论 成功地建立了基于人孕烷X受体的UGT1A1的报告基因模型,为人孕烷X受体激活剂的体外筛选提供了一种有效的方法。     

人尿苷二磷酸葡糖醛酸转移酶(UGT)亚型参与反式-白藜芦醇体外代谢的研究

目的:研究参与反式-白藜芦醇(trans-resveratrol,TR)Ⅱ相代谢的主要尿苷二磷酸葡糖醛酸转移酶(UGTs)亚型。方法:在体外对反式-白藜芦醇与12种主要的人重组UGT亚型进行温孵,采用液相色谱-质谱法测定其葡萄糖醛酸代谢产物,对其结构做初步分析,并考察不同UGT亚型对白藜芦醇代谢产物生成速率的影响。结果:在体外代谢系统中,白藜芦醇被UGT催化生成2种单葡萄糖醛酸代谢产物M-1和M-2,初步推断其为白藜芦醇-4’和3-葡萄糖醛酸化物,亚型UGT1A1,1A3,1A8,1A9,1A10都参与了催化产生代谢产物M-1和M-2,UGT1A6,1A7仅对M-2的生成有贡献。随着底物浓度的升高,UGT1A1,1A10催化底物产生M-1和M-2及1A8催化底物产生M-2的速率都减慢,出现了底物抑制现象。结论:UGT1A1,1A8,1A9,1A10参与了代谢产物M-1的产生,其中UGT1A9的贡献最大,UGT1A1,1A6,1A7,1A8,1A9,1A10参与了代谢产物M-2的产生,其中1A1和1A9贡献最大,UGT1A3也有少量参与2种代谢物的产生,其他亚型几乎都不参与反式-白藜芦醇的Ⅱ相代谢反应。     

Inhibitory potential of three Yin-tonification herbal formulas on the activities of human major cytochrome P450 and UDP-glucuronosyltransferases isozymes in vitro

OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.     

Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP‐Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes

The aqueous stem bark extract of Mangifera indica L. (MSBE) has been reported to have antioxidant, anti‐inflammatory and analgesic properties. In previous studies, we showed that MSBE and mangiferin, its main component, lower the activity of some cytochrome P‐450 (P450) enzymes in rat hepatocytes and human liver microsomes. In the present study, the effects of MSBE and mangiferin on several P450 enzymes and UDP‐glucuronosyltransferases (UGTs) in human‐cultured hepatocytes have been examined. After hepatocytes underwent a 48‐h treatment with sub‐cytotoxic concentrations of the products (50–250 µg/mL), a concentration‐dependent decrease of the activity of the five P450 enzymes measured (CYP1A2, 2A6, 2C9, 2D6 and 3A4) was observed. For all the activities, a reduction of at least 50% at the highest concentration (250 µg/mL) was observed. In addition, UGT activities diminished. MSBE considerably reduced UGT1A9 activity (about 60% at 250 µg/mL) and lesser effects on the other UGTs. In contrast, 250 µg/mL mangiferin had greater effects on UGT1A1 and 2B7 than on UGT1A9 (about 55% vs. 35% reduction, respectively). Quantification of specific mRNAs revealed reduced CYP3A4 and 3A5 mRNAs content, and an increase in CYP1A1, CYP1A2, UGT1A1 and UGT1A9 mRNAs. No remarkable effects on the CYP2A6, 2B6, 2C9, 2C19, 2D6 and 2E1 levels were observed. Our results suggest that the activity and/or expression of major P450 and UGT enzymes is modulated by MSBE and that potential herb–drugs interactions could arise after a combined intake of this extract with conventional medicines. Therefore, the potential safety risks of this natural product derived by altering the ADMET properties of co‐administered drugs should be examined. Copyright © 2012 John Wiley & Sons, Ltd.     

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai‐hua Qian‐hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug‐metabolizing enzymes uridine 5'‐diphospho‐glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro–in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (K_i) and in vivo exposure level of PA. Praeruptorin A (100 μM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 μM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (K_i) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 μM, respectively. The [I]/K_i value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7‐catalyzed metabolism is very necessary. Copyright © 2016 John Wiley & Sons, Ltd.     

Glycyrrhetinic Acid Exhibits Strong Inhibitory Effects Towards UDP‐Glucuronosyltransferase (UGT) 1A3 and 2B7

The aim of the present study is to evaluate the inhibitory effects of liver UDP‐glucuronosyltransferases (UGTs) by glycyrrhizic acid and glycyrrhetinic acid, which are the bioactive ingredients isolated from licorice. The results showed that glycyrrhetinic acid exhibited stronger inhibition towards all the tested UGT isoforms, indicating that the deglycosylation process played an important role in the inhibitory potential towards UGT isoforms. Furthermore, the inhibition kinetic type and parameters were determined for the inhibition of glycyrrhetinic acid towards UGT1A3 and UGT2B7. Data fitting using Dixon and Lineweaver‐Burk plots demonstrated that the inhibition of UGT1A3 and UGT2B7 by glycyrrhetinic acid was best fit to competitive and noncompetitive type, respectively. The second plot using the slopes from Lineweaver‐Burk plots versus glycyrrhetinic acid concentrations was employed to calculate the inhibition kinetic parameters (K_i), and the values were calculated to be 0.2 and 1.7 μM for UGT1A3 and UGT2B7, respectively. All these results remind us the possibility of UGT inhibition‐based herb–drug interaction. However, the explanation of these in vitro parameters should be paid more caution due to complicated factors, including the probe substrate‐dependent UGT inhibition behaviour, environmental factors affecting the abundance of herbs' ingredients, and individual difference of pharmacokinetic factors. Copyright © 2012 John Wiley & Sons, Ltd.     

Inhibition of UDP‐Glucuronosyltransferases (UGTs) Activity by constituents of Schisandra chinensis

Structure–activity relationship for the inhibition of Schisandra chinensis's ingredients toward (Uridine‐Diphosphate) UDP‐glucuronosyltransferases (UGTs) activity was performed in the present study. In vitro incubation system was employed to screen the inhibition capability of S. chinensis's ingredients, and in silico molecular docking method was carried out to explain possible mechanisms. At 100 μM of compounds, the activity of UGTs was inhibited by less than 90% by schisandrol A, schisandrol B, schisandrin, schisandrin C, schisantherin A, gomisin D, and gomisin G. Schisandrin A exerted strong inhibition toward UGT1A1 and UGT1A3, with the residual activity to be 7.9% and 0% of control activity. Schisanhenol exhibited strong inhibition toward UGT2B7, with the residual activity to be 7.9% of control activity. Gomisin J of 100 μM inhibited 91.8% and 93.1% of activity of UGT1A1 and UGT1A9, respectively. Molecular docking prediction indicated different hydrogen bonds interaction resulted in the different inhibition potential induced by subtle structure alteration among schisandrin A, schisandrin, and schisandrin C toward UGT1A1 and UGT1A3: schisandrin A > schisandrin > schisandrin C. The detailed inhibition kinetic evaluation showed the strong inhibition of gomisin J toward UGT1A9 with the inhibition kinetic parameter (K_i) to be 0.7 μM. Based on the concentrations of gomisin J in the plasma of the rats given with S. chinensis, high herb–drug interaction existed between S. chinensis and drugs mainly undergoing UGT1A9‐mediated metabolism. In conclusion, in silico‐in vitro method was used to give the inhibition information and possible inhibition mechanism for S. chinensis's components toward UGTs, which guide the clinical application of S. chinensis. Copyright © 2015 John Wiley & Sons, Ltd.     

血府逐瘀汤对大鼠肝组织内CYPs, UGTs和GSTs基因表达的影响

目的: 研究血府逐瘀汤对大鼠肝组织内药物代谢酶细胞色素P450（CYPs, cytochrome P450）,谷胱甘肽-S-转移酶GSTs,glutathione S transferase）和尿甘二磷酸葡糖醛酸转移酶（UGTs,UDP-glucuronosyl transferase）基因表达的影响。 方法: 将25只大鼠随机分为5组,每组5只。大鼠按3.51,7.02,14.04 g·kg^-1分别ig给予血府逐瘀汤水提物,空白组给等体积纯净水,连续给药15 d,苯巴比妥钠于第13天按80 mg·kg^-1腹腔注射,连续3 d。取200 mg左右肝脏,用逆转录-实时荧光定量PCR法检测肝组织内的CYP基因CYP1A1,CYP1A2,CYP2B1,CYP2C11,CYP2E1,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GST基因GSTA2,GSTM1,GSTp1和UGT基因UGT1A1,UGT2B1的表达情况。 结果: 与空白组比较,苯巴比妥钠组（阳性组）可明显诱导CYP2B1,CYP3A1,CYP3A2,GSTA2和UGT2B1基因表达（84.57,5.44,5.11,7.76,13.27倍,P<0.01）;血府逐瘀汤3.51,7.02 g·kg^-1分别诱导GSTA2和CYP1A1的基因表达（1.54倍,P<0.05;57.92倍,P<0.05）;14.04 g·kg^-1明显抑制CYP2C11的基因表达（55%,P<0.05）;3.51,7.02,14.04 g·kg^-13个剂量对GSTM1有明显的抑制作用（53%,55%,51%,P<0.05）;血府逐瘀汤对CYP1A2,CYP2B1,CYP2E1,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GSTp1,UGT1A1和UGT2B1的基因表达无明显影响。 结论: 血府逐瘀汤可明显诱导CYP1A1,GSTA2基因的表达,对CYP2C11,GSTM1的基因有明显的抑制作用,而对其余的亚型无显著影响。提示临床上与CYP1A1及CYP2C11的底物合用时,要注意药物代谢性相互作用,且其可能参与肝脏对毒物、致癌物以及其他物质的解毒和排泄,对多种恶性肿瘤的发生可能起到一定的作用。