CYP2C亚家族药物代谢酶基因多态性及功能研究
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摘要
细胞色素P450(CYP)2C亚家族包括CYP2C9、CYP2C19、CYP2C8等,都是重要的药物代谢酶。据估计,CYP2C9负责代谢清除15%的在人体内的经过一相代谢的药物。而CYP2C19也代谢很多临床重要药物。他们的基因的多态性和在体内受诱导或抑制的程度被认为决定了相关药物代谢的个体和种族差异。
在本文的第一部分研究中,一个新的CYP2C9等位基因CYP2C9~*13(Leu90Pro单氨基酸取代突变)被首次识别,约2.0%的中国汉族人是本突变的杂合携带者。CYP2C9~*13酶活力较野生型显著下降。计算机结构模拟研究表明这主要由于底物口袋体积的缩小和形状的改变。
本文第二部分研究了CYP2C9和CYP2C19基因多态性与受试者格列奇特代谢能力减弱的相关性,首次发现是CYP2C19基因多态性决定了格列奇特代谢速度个体差异。本文也研究了CYP2C9和CYP2C19基因多态性对人体中卡利普多和格列本尿代谢速度的影响。
第三部分研究了CYP2C9受抑制的特性,发现大多数黄酮类和黄酮醇类化合物都能在体外强烈抑制CYP2C9,计算机结构模拟研究核定点突变证明抑制位点有两处,分别在底物结合位置和别构位点上;另外本文也研究了CYP2C9多态性对其受抑制能力的影响。
Cytochrome P450s(CYPs) are the most important superfamily of biotransformation enzymes that are involved in oxidative metabolism of a wide variety of endogenous and exogenous compounds.The CYP2C subfamily of human liver P450 isozymes is of major importance in drug metabolism and plays a key role in the drugs pharmacological and toxicological effects.CYP2C9 is the most abundant 2C subfamily isozyme in human liver which is responsible for the metabolic clearance of a wide variety of the therapeutic agents,estimated up to 16%of drugs in current clinical used.CYP2C19 ranks amongst the most important drug metabolizing enzymes in human,too.
In the first part of the article,CYP2C9*13 was found in a person with lornoxicam half-life of about 105 hours was markedly longer than that of other subjects.This new variant CYP2C9 allele involving a T269C transversion in exon 2 that leads to a Leu90Pro substitution in the encoded protein(CYP2C9*13).Frequency analysis in 147 unrelated Chinese males indicated approximately 2%of the Chinese population carry the allele.Then, the pharmacokinetics of tolbutamide in the PM subjects was investigated, and he was found to be a phenotypically poor metabolizer of tolbutamide as well.Since tolbutamide is widely accepted as a probe substrate for the assessment of hepatic CYP2C9 activity in vivo,this study confirms that the study subject has severely impaired CYP2C9 catalytic efficiency.This novel CYP2C9 allele was correlated with reduced plasma clearance of both lornoxicam and tolbutamide.In order to explore the structure-activity relationship of CYP2C9*13,the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1(PDB code 1R9O) by molecular dynamics simulations.The structure change caused by Leu90Pro replacement is revealed and used to explain the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lornoxicam.The trans configuration of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified.The backbone of residues 106-108 in CYP2C9*13 turns over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type,which is believed to be the dominant mechanism of the catalytic activity reduction.Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al.identifies the most important residues for enzyme-substrate complexes.
In the second part of the article,we investigated the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release(MR) in healthy Chinese subjects.In a single-dose pharmacokinetic study,24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose.In a multiple-dose pharmacokinetic study,17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose.The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method.CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis.In the single-dose study,no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1,*1/*3 and *1/*13 subjects.In contrast,the AUC_(0-∞) of gliclazide was significantly increased by 3.4-fold [95%confidence interval(CI) 2.5,4.7;P＜0.01]in CYP2C19 poor metabolizer(PM) subjects compared with CYP2C19*1 homozygotes.The half-life(t_(1/2)) was prolonged from 15.1 to 44.5 h(P＜0.01).Similar differences were found in the multiple-dose study.The parameters of gliclazide AUCss,AUC_(0-∞) and C_(max) were 3.4-fold(95%CI 2.9,4.0), 4.5-fold(95%CI 3.8,5.4) and 2.9-fold(95%CI 2.4,3.4) increased(P＜0.01) in CYP2C19 PM subjects,respectively,compared with CYP2C19*1 homozygotes,and t_(1/2) was increased from 13.5 to 24.6 h(P＜0.01).The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.
We also investigate the pharmacokinetics of carisoprodol at dosage of 350 mg and 700 mg and the influence of CYP2C19 polymorphism on its pharmacokinetics in healthy Chinese volunteers.In a randomized, two-period crossover study,12 healthy Chinese male volunteers were administered carisoprodol 350 mg or 700 mg,and plasma was sampled for 36 h post dose.The plasma concentrations of carisoprodol and it main metabolite meprobamate were measured using a validated LC/MS/MS method.CYP2C19 genotyping was conducted on these volunteers by PCR-RFLP analysis.The study indicates that saturation of metabolism may occur at higher dose of carisoprodol.CYP2C19 polymorphism influences the pharmacokinetics of carisoprodol markedly in Chinese volunteers.
We investigate the impact of CYP2C9*3 on the pharmacokinetics of glibenclamide.CYP2C9*3 greatly affects both the pharmacokinetic profiles of glibenclamide.The elimination of glibenclamide significantly decreased in subjectswith CYP2C9*1/*3 genotype.
In the third part of the article,an in vitro investigation of the inhibition of cytochrome p450 2C9(CYP2C9) by a series of flavonoids was described. In recent years,flavonoid intake in the form of dietary supplements and plant extracts has been steadily increasing.Some clinical studies have demonstrated that flavonoids may alter drug metabolism.Moreover,in China,some flavonoids are administered intravenously as drugs.In the current investigation,using CYP2C9 substrate diclofenac,one of the most commonly employed probes for determining CYP2C9 catalytic activity,a number of flavones(flavone,6-hydroxyflavone,7-hydroxyflavone,chrysin, baicalein,apigenin,luteolin,scutellarein,wogonin) and flavonols(galangin, fisetin,kaempferol,morin,quercetin) were shown to substantially inhibit CYP2C9-mediated diclofenac 4'-hydroxylation in CYP2C9 RECO~(?) system (K_i≤2.2μM) with galangin being the most potent inhibitor(K_i=0.15μM). These findings raise concerns about possible drug-drug interactions between supplements,remedies and drugs containing flavonoids and the some 100 therapeutic drugs metabolized by CYP2C9.
Cytochrome P450 noncompetitive inhibitors have been reported widely, particularly to CYP1A2 and CYP2C9,with molecular basis unknown.In the current investigation,most flavones and flavonols are found to be competitive inhibitor,indicating they bind to the substrate-binding site of CYP2C9.On the basis of docking simulation studies using the 1R9O crystal structure,this binding site is shown to be close to the heme and is the same site as flurbiprofen in the 1R9O crystal structure.On the other hand, noncompetitive inhibitor 6-hydroxyflavone binds to a site further from the heme and oriented away from the other flavones and flavonols,but consistent with the reported warfarin allosteric binding site revealed by the crystal structure of 1OG5,and also consistent with the reported dapsone allosteric site that can activate CYP2C9-mediated flurbiprofen 4'-hydroxylation.
To confirm the role of Phe 100 in the noncompetitive binding of 6-hydroxyflavone to CYP2C9,site-directed mutagenesis was constructed generating CYP2C9 variants Phe100Asp and Phe100Trp.These mutants showed diclofenac 4'-hydroxylase activity similar to that of CYP2C9.1 and were both competitively inhibited by 6-hydroxyflavone.This demonstrates the presence of a direct interaction between 6-hydroxyflavone and Phe 100 in the CYP2C9 noncompetitive inhibition.The binding sites of flavones and flavonols to CYP2C9 determine their inhibiting mechanism.
在本文的第一部分研究中,一个新的CYP2C9等位基因CYP2C9~*13(Leu90Pro单氨基酸取代突变)被首次识别,约2.0%的中国汉族人是本突变的杂合携带者。CYP2C9~*13酶活力较野生型显著下降。计算机结构模拟研究表明这主要由于底物口袋体积的缩小和形状的改变。
本文第二部分研究了CYP2C9和CYP2C19基因多态性与受试者格列奇特代谢能力减弱的相关性,首次发现是CYP2C19基因多态性决定了格列奇特代谢速度个体差异。本文也研究了CYP2C9和CYP2C19基因多态性对人体中卡利普多和格列本尿代谢速度的影响。
第三部分研究了CYP2C9受抑制的特性,发现大多数黄酮类和黄酮醇类化合物都能在体外强烈抑制CYP2C9,计算机结构模拟研究核定点突变证明抑制位点有两处,分别在底物结合位置和别构位点上;另外本文也研究了CYP2C9多态性对其受抑制能力的影响。
Cytochrome P450s(CYPs) are the most important superfamily of biotransformation enzymes that are involved in oxidative metabolism of a wide variety of endogenous and exogenous compounds.The CYP2C subfamily of human liver P450 isozymes is of major importance in drug metabolism and plays a key role in the drugs pharmacological and toxicological effects.CYP2C9 is the most abundant 2C subfamily isozyme in human liver which is responsible for the metabolic clearance of a wide variety of the therapeutic agents,estimated up to 16%of drugs in current clinical used.CYP2C19 ranks amongst the most important drug metabolizing enzymes in human,too.
In the first part of the article,CYP2C9*13 was found in a person with lornoxicam half-life of about 105 hours was markedly longer than that of other subjects.This new variant CYP2C9 allele involving a T269C transversion in exon 2 that leads to a Leu90Pro substitution in the encoded protein(CYP2C9*13).Frequency analysis in 147 unrelated Chinese males indicated approximately 2%of the Chinese population carry the allele.Then, the pharmacokinetics of tolbutamide in the PM subjects was investigated, and he was found to be a phenotypically poor metabolizer of tolbutamide as well.Since tolbutamide is widely accepted as a probe substrate for the assessment of hepatic CYP2C9 activity in vivo,this study confirms that the study subject has severely impaired CYP2C9 catalytic efficiency.This novel CYP2C9 allele was correlated with reduced plasma clearance of both lornoxicam and tolbutamide.In order to explore the structure-activity relationship of CYP2C9*13,the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1(PDB code 1R9O) by molecular dynamics simulations.The structure change caused by Leu90Pro replacement is revealed and used to explain the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lornoxicam.The trans configuration of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified.The backbone of residues 106-108 in CYP2C9*13 turns over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type,which is believed to be the dominant mechanism of the catalytic activity reduction.Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al.identifies the most important residues for enzyme-substrate complexes.
In the second part of the article,we investigated the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release(MR) in healthy Chinese subjects.In a single-dose pharmacokinetic study,24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose.In a multiple-dose pharmacokinetic study,17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose.The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method.CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis.In the single-dose study,no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1,*1/*3 and *1/*13 subjects.In contrast,the AUC_(0-∞) of gliclazide was significantly increased by 3.4-fold [95%confidence interval(CI) 2.5,4.7;P＜0.01]in CYP2C19 poor metabolizer(PM) subjects compared with CYP2C19*1 homozygotes.The half-life(t_(1/2)) was prolonged from 15.1 to 44.5 h(P＜0.01).Similar differences were found in the multiple-dose study.The parameters of gliclazide AUCss,AUC_(0-∞) and C_(max) were 3.4-fold(95%CI 2.9,4.0), 4.5-fold(95%CI 3.8,5.4) and 2.9-fold(95%CI 2.4,3.4) increased(P＜0.01) in CYP2C19 PM subjects,respectively,compared with CYP2C19*1 homozygotes,and t_(1/2) was increased from 13.5 to 24.6 h(P＜0.01).The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.
We also investigate the pharmacokinetics of carisoprodol at dosage of 350 mg and 700 mg and the influence of CYP2C19 polymorphism on its pharmacokinetics in healthy Chinese volunteers.In a randomized, two-period crossover study,12 healthy Chinese male volunteers were administered carisoprodol 350 mg or 700 mg,and plasma was sampled for 36 h post dose.The plasma concentrations of carisoprodol and it main metabolite meprobamate were measured using a validated LC/MS/MS method.CYP2C19 genotyping was conducted on these volunteers by PCR-RFLP analysis.The study indicates that saturation of metabolism may occur at higher dose of carisoprodol.CYP2C19 polymorphism influences the pharmacokinetics of carisoprodol markedly in Chinese volunteers.
We investigate the impact of CYP2C9*3 on the pharmacokinetics of glibenclamide.CYP2C9*3 greatly affects both the pharmacokinetic profiles of glibenclamide.The elimination of glibenclamide significantly decreased in subjectswith CYP2C9*1/*3 genotype.
In the third part of the article,an in vitro investigation of the inhibition of cytochrome p450 2C9(CYP2C9) by a series of flavonoids was described. In recent years,flavonoid intake in the form of dietary supplements and plant extracts has been steadily increasing.Some clinical studies have demonstrated that flavonoids may alter drug metabolism.Moreover,in China,some flavonoids are administered intravenously as drugs.In the current investigation,using CYP2C9 substrate diclofenac,one of the most commonly employed probes for determining CYP2C9 catalytic activity,a number of flavones(flavone,6-hydroxyflavone,7-hydroxyflavone,chrysin, baicalein,apigenin,luteolin,scutellarein,wogonin) and flavonols(galangin, fisetin,kaempferol,morin,quercetin) were shown to substantially inhibit CYP2C9-mediated diclofenac 4'-hydroxylation in CYP2C9 RECO~(?) system (K_i≤2.2μM) with galangin being the most potent inhibitor(K_i=0.15μM). These findings raise concerns about possible drug-drug interactions between supplements,remedies and drugs containing flavonoids and the some 100 therapeutic drugs metabolized by CYP2C9.
Cytochrome P450 noncompetitive inhibitors have been reported widely, particularly to CYP1A2 and CYP2C9,with molecular basis unknown.In the current investigation,most flavones and flavonols are found to be competitive inhibitor,indicating they bind to the substrate-binding site of CYP2C9.On the basis of docking simulation studies using the 1R9O crystal structure,this binding site is shown to be close to the heme and is the same site as flurbiprofen in the 1R9O crystal structure.On the other hand, noncompetitive inhibitor 6-hydroxyflavone binds to a site further from the heme and oriented away from the other flavones and flavonols,but consistent with the reported warfarin allosteric binding site revealed by the crystal structure of 1OG5,and also consistent with the reported dapsone allosteric site that can activate CYP2C9-mediated flurbiprofen 4'-hydroxylation.
To confirm the role of Phe 100 in the noncompetitive binding of 6-hydroxyflavone to CYP2C9,site-directed mutagenesis was constructed generating CYP2C9 variants Phe100Asp and Phe100Trp.These mutants showed diclofenac 4'-hydroxylase activity similar to that of CYP2C9.1 and were both competitively inhibited by 6-hydroxyflavone.This demonstrates the presence of a direct interaction between 6-hydroxyflavone and Phe 100 in the CYP2C9 noncompetitive inhibition.The binding sites of flavones and flavonols to CYP2C9 determine their inhibiting mechanism.
引文
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48 Morse RM, Chua L. Carisoprodol dependence: a case report. Am J Drug Alcohol Abuse 1978; 5:527-530.
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50 Bramness JG, Skurtveit S, Fauske L, Grung M, Molven A, M0rland J, Steen VM.Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics.2003 Jul; 13:383-8.
51 Wang SL, Huang J, Lai MD, Tsai JJ. Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 1995; 5:37-42.
52 MouraMR, de Nucci G, Rath S, et al. LC-APCI-MS-MS methodology for determination of glybenclamide in human plasma [J]. Anal Bioanal Chem , 2004,378 (2) : 499 -503.
53 Su J, Chen XY, Duan XT, Zhang YF, Zhong DF. Rapid determination of gliclazide in human plasma by LC/MS/MS. Chinese Pharmaceut J 2006; 41:864-7.
54 Yifan Zhang, Dayong Si, Xiaoyan Chen, Nan Lin, Yingjie Guo, Hui Zhou, Dafang Zhong*, Impacts of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. The British Journal of Clinical Pharmacology, 2007 Jul;64(1):67-74.
55 Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brockmoller J. Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005; 44: 1209-25.
56 Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K,Robertson P Jr, Koch P, Antonian L, Wagner GYuL, Parkinson A. Effects of prototypical microsomal enzyme inducers in cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 2003; 31: 421-31.
57 Park JY, Kim KA, Park PW, Park CW, Shin JG. Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide. Clin Pharmacol Ther 2003;74: 334-40.
58 Maekawa K, Fukushima-Uesaka H, Tohkin M, Hasegawa R, Kajio H, Kuzuya N,Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Saito Y, Sawada J.Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese. Pharmacogenet Genomics 2006; 16: 497-514.
59 Bramness JG, Furu K, Engeland A, Skurtveit S. Carisoprodol use and abuse in Norway. A pharmacoepidemiological study. Br J Clin Pharmacol 2007; 64: 210-8.
60 Tiller PR, Land AP, Jardine I, et al. App lication of liquid chromatography-mass spectrometry analyses to the characterization of novel glyburide metabolites formed in vitro. J Chrom atogr A, 1998, 794:15-25.
61 Cermak R and Wolffram S (2006) The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms. Curr Drug Metab 7(7):729-744.
62 Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56(11):317-333.
63 Hertog MGL, Hollman PCH and van de Putte B (1993) Content of potentially anticarcinogenic flavonoids of tea infusions, wines, and fruit juices. J Agric Food Chem 41(8): 1242-1246.
64 Peterson J and Dwyer J (1998) Flavonoids: Dietary occurrence and biochemical activity. Nutrition Research 18(12): 1995-2018.
65 Peng WX, Li HD and Zhou HH (2003) Effect of daidzein on CYP1A2 activity and pharmacokinetics of theophylline in healthy volunteers. Eur J Clin Pharmacol 59(3):237-241.
66 Rajnarayana K, Reddy MS and Krishna DR (2003) Diosmin pretreatment affects bioavailability of metronidazole. Eur J Clin Pharmacol 58(12):803-807.
67 Foti RS, Wahlstrom JL and Wienkers LC (2007) The in vitro drug interaction potential of dietary supplements containing multiple herbal components. Drug Metab Dispos 35(2): 185-188.
68 Kim JY, Lee S, Kim DH, Kim BR, Park R and Lee BM (2002) Effects of flavonoids isolated from Scutellariae radix on cytochrome P-450 activities in human liver microsomes. J Toxicol Environ Health A 65(5-6):373-381.
69 Kumar V, Wahlstrom JL, Rock DA, Warren CJ, Gorman LA and Tracy TS (2006) CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 34(12): 1966-1975.
70 von Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P and Greenblatt DJ (2004) Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol 56(8): 1039-1044.
71 Sridar C, Goosen TC, Kent UM, Williams JA and Hollenberg PF (2004) Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 32(6):587-594.
72 Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP and Zhou H (2005b) Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans. Drug Metab Dispos 33(6):749-753.
73 Choi JS, Choi BC and Choi KE (2004) Effect of quercetin on the pharmacokinetics of oral cyclosporine. Am J Health Syst Pharm 61(22):2406-2409.
74 Liu KH, Kim MJ, Jeon BH, Shon JH, Cha IJ, Cho KH, Lee SS and Shin JG (2006) Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herba. J Clin Pharm Ther 31(1):83-91.
75 Cermak R (2008) Effect of dietary flavonoids on pathways involved in drug metabolism. Expert Opin Drug Metab Toxicol 4(1): 17-35.
76 Manach C, Williamson G, Morand C, Scalbert A and Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81(1 Suppl):230S-242S.
77 Salsali M, Holt A and Baker GB (2004) Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19,CYP2C9, and CYP2D6. Cell Mol Neurobiol 24(l):63-76.
78 Bourrie M, Meunier V, Berger Y and Fabre G (1999) Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes. Drug Metab Dispos 27(2):288-296.
79 Nakajima M, Yoshida R, Shimada N, Yamazaki H and Yokoi T (2001) Inhibition and inactivation of human cytochrome P450 isofonns by phenethyl isothiocyanate.Drug Metab Dispos 29(8): 1110-1113.
80 Zhang JW, Liu Y, Li W, Hao DC and Yang L (2006) Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes. Eur J Clin Pharmacol 62(7):497-502.
81 Hummel MA, Dickmann LJ, Rettie AE, Haining RL and Tracy TS (2004a) Differential activation of CYP2C9 variants by dapsone. Biochem Pharmacol 67(10):1831-1841.
82 Hummel MA, Gannett PM, Aguilar JS and Tracy TS (2004b) Effector-mediated alteration of substrate orientation in cytochrome P450 2C9. Biochemistry 43(22):7207-7214.
83 de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA.The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419-22.
84 de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA.Identification of a new genetic defect responsible for the polymorphism of (s)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994;46:594-8.
85 Ferguson RJ, de Morais SM, Benhamou S, et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 1998;284:356-61.
86 Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989;43:53-76.
87 Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphism in Far Eastern Oriental Subjects: Japanese versus mainland Chinese.Clin Pharmacol Ther 1989;46:198-207.
88 Taylor AR, Brownsill RD, Grandon H, Lefoulon F, Petit A, LuijtenW, Kopelman PG, Walther B. Synthesis of putative metabolism and investigation of the metabolic fate of gliclazide,[1-(3-azabicyclo(3,3,0) oct-3-yl)-3-(4--methylphenylsulfonyl)urea],in diabetic patients.Drug Metab Dispos 1996;24:55-64.
89 Tong YIN,Keiko MAEKAWA,Kei KAMIDE,Yoshiro SAITO,Hironori HANADA,Kotaro MIYASHITA,Yoshihiro KOKUBO,Yasuhisa AKAIWA,Ryoichi OTSUBO,Kazuyuki NAGATSUKA,Toshiho OTSUKI,Takeshi HORIO,Shin TAKIUCHI,Yuhei KAWANO,Kazuo MINEMATSU,Hiroaki NARITOMI,Hitonobu TOMOIKE,Jun-ichi SAWADA,and Toshiyuki MIYATA1),Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan,Hypertens Res Vol.31,No.8(2008),1149-57
90 Bae,J.W.;Kim,H.K.;Kim,J.H.;Yang,S.I.;Kim,M.J.;Jang,C.G.;Park,Y.S.and Lee,S.Y.(2005) Allele and genotype frequencies of CYP2C9 in a Korean population.Br J Clin Pharmacol.60,418-422.
91 Allan E.Rettie and Jeffrey P.Jones Clinical and toxicological relevance of CYP2C9:drug-drug interactions and pharmacogenetics.Annu.Rev.Pharmacol.Toxicol.2005.45:477-94
92 何震宇 潘伟 崔炳权 杨红,广东人群CYP2C9基因T269C位点多态性研究《广东药学院学报》2006年22卷3期
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30 Veenstra, D. L.; Blough, D. K.; Higashi, M. K.; Farm, F. M.; Srinouanprachan, S.;Rieder, M. J. and Rettie, A. E. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Ther.2005,77,353-364.
31 Lee CR, Goldstein JA, Pieper JA.Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics.2002;12:251-63.
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49 Rust GS, Hatch R, Gums JG. Carisoprodol as a drug of abuse. Arch Fam Med 1993; 2:429-432.
50 Bramness JG, Skurtveit S, Fauske L, Grung M, Molven A, M0rland J, Steen VM.Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics.2003 Jul; 13:383-8.
51 Wang SL, Huang J, Lai MD, Tsai JJ. Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 1995; 5:37-42.
52 MouraMR, de Nucci G, Rath S, et al. LC-APCI-MS-MS methodology for determination of glybenclamide in human plasma [J]. Anal Bioanal Chem , 2004,378 (2) : 499 -503.
53 Su J, Chen XY, Duan XT, Zhang YF, Zhong DF. Rapid determination of gliclazide in human plasma by LC/MS/MS. Chinese Pharmaceut J 2006; 41:864-7.
54 Yifan Zhang, Dayong Si, Xiaoyan Chen, Nan Lin, Yingjie Guo, Hui Zhou, Dafang Zhong*, Impacts of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. The British Journal of Clinical Pharmacology, 2007 Jul;64(1):67-74.
55 Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brockmoller J. Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005; 44: 1209-25.
56 Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K,Robertson P Jr, Koch P, Antonian L, Wagner GYuL, Parkinson A. Effects of prototypical microsomal enzyme inducers in cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 2003; 31: 421-31.
57 Park JY, Kim KA, Park PW, Park CW, Shin JG. Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide. Clin Pharmacol Ther 2003;74: 334-40.
58 Maekawa K, Fukushima-Uesaka H, Tohkin M, Hasegawa R, Kajio H, Kuzuya N,Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Saito Y, Sawada J.Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese. Pharmacogenet Genomics 2006; 16: 497-514.
59 Bramness JG, Furu K, Engeland A, Skurtveit S. Carisoprodol use and abuse in Norway. A pharmacoepidemiological study. Br J Clin Pharmacol 2007; 64: 210-8.
60 Tiller PR, Land AP, Jardine I, et al. App lication of liquid chromatography-mass spectrometry analyses to the characterization of novel glyburide metabolites formed in vitro. J Chrom atogr A, 1998, 794:15-25.
61 Cermak R and Wolffram S (2006) The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms. Curr Drug Metab 7(7):729-744.
62 Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56(11):317-333.
63 Hertog MGL, Hollman PCH and van de Putte B (1993) Content of potentially anticarcinogenic flavonoids of tea infusions, wines, and fruit juices. J Agric Food Chem 41(8): 1242-1246.
64 Peterson J and Dwyer J (1998) Flavonoids: Dietary occurrence and biochemical activity. Nutrition Research 18(12): 1995-2018.
65 Peng WX, Li HD and Zhou HH (2003) Effect of daidzein on CYP1A2 activity and pharmacokinetics of theophylline in healthy volunteers. Eur J Clin Pharmacol 59(3):237-241.
66 Rajnarayana K, Reddy MS and Krishna DR (2003) Diosmin pretreatment affects bioavailability of metronidazole. Eur J Clin Pharmacol 58(12):803-807.
67 Foti RS, Wahlstrom JL and Wienkers LC (2007) The in vitro drug interaction potential of dietary supplements containing multiple herbal components. Drug Metab Dispos 35(2): 185-188.
68 Kim JY, Lee S, Kim DH, Kim BR, Park R and Lee BM (2002) Effects of flavonoids isolated from Scutellariae radix on cytochrome P-450 activities in human liver microsomes. J Toxicol Environ Health A 65(5-6):373-381.
69 Kumar V, Wahlstrom JL, Rock DA, Warren CJ, Gorman LA and Tracy TS (2006) CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 34(12): 1966-1975.
70 von Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P and Greenblatt DJ (2004) Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol 56(8): 1039-1044.
71 Sridar C, Goosen TC, Kent UM, Williams JA and Hollenberg PF (2004) Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 32(6):587-594.
72 Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP and Zhou H (2005b) Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans. Drug Metab Dispos 33(6):749-753.
73 Choi JS, Choi BC and Choi KE (2004) Effect of quercetin on the pharmacokinetics of oral cyclosporine. Am J Health Syst Pharm 61(22):2406-2409.
74 Liu KH, Kim MJ, Jeon BH, Shon JH, Cha IJ, Cho KH, Lee SS and Shin JG (2006) Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herba. J Clin Pharm Ther 31(1):83-91.
75 Cermak R (2008) Effect of dietary flavonoids on pathways involved in drug metabolism. Expert Opin Drug Metab Toxicol 4(1): 17-35.
76 Manach C, Williamson G, Morand C, Scalbert A and Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81(1 Suppl):230S-242S.
77 Salsali M, Holt A and Baker GB (2004) Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19,CYP2C9, and CYP2D6. Cell Mol Neurobiol 24(l):63-76.
78 Bourrie M, Meunier V, Berger Y and Fabre G (1999) Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes. Drug Metab Dispos 27(2):288-296.
79 Nakajima M, Yoshida R, Shimada N, Yamazaki H and Yokoi T (2001) Inhibition and inactivation of human cytochrome P450 isofonns by phenethyl isothiocyanate.Drug Metab Dispos 29(8): 1110-1113.
80 Zhang JW, Liu Y, Li W, Hao DC and Yang L (2006) Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes. Eur J Clin Pharmacol 62(7):497-502.
81 Hummel MA, Dickmann LJ, Rettie AE, Haining RL and Tracy TS (2004a) Differential activation of CYP2C9 variants by dapsone. Biochem Pharmacol 67(10):1831-1841.
82 Hummel MA, Gannett PM, Aguilar JS and Tracy TS (2004b) Effector-mediated alteration of substrate orientation in cytochrome P450 2C9. Biochemistry 43(22):7207-7214.
83 de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA.The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419-22.
84 de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA.Identification of a new genetic defect responsible for the polymorphism of (s)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994;46:594-8.
85 Ferguson RJ, de Morais SM, Benhamou S, et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 1998;284:356-61.
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