银杏叶片对人药物代谢酶CYP1A2、CYP2A6、NAT2和XO的影响
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摘要
目的:药物代谢酶CYP1A2、CYP2A6、NAT2和XO在药物代谢和前致癌物激活的过程中均起着重要的作用。CYP1A2、CYP2A6、NAT2和XO的活性与许多药物的疗效或毒性以及一些肿瘤的易感性密切相关;它们在人群中的分布存在种族差异,其活性也有明显的个体差异,四种酶不同活性状态的存在对化学物质的体内转化必定产生一定的影响。本课题以健康受试者为研究对象,从代谢表型探讨银杏叶片与药物代谢酶CYP1A2、CYP2A6、NAT2和XO的关系,预测银杏叶片与常用药物的相互作用,以便指导临床医师合理用药,预防和减轻药物间的相互作用,最大限度的提高药物的有效性和安全性。
方法:以咖啡因作为药物代谢酶CYP1A2、CYP2A6、NAT2和XO的探针药物,为保证应用咖啡因代谢探针的正确性,采用岛津Shim-pack VP-ODS柱(4.6mm×150mm,5μm),岛津Shim-pack C18预柱,流动相为乙腈(A相),0.05%醋酸(B相),0-24min流动相B的比例从2.5%线性增加至10%,流速为1.0mL.min~(-1),柱温25℃,检测波长为280nm,建立了反相高效液相色谱(RP-HPLC)测定尿液中咖啡因代谢物的方法,采用该法测定30名受试者分别服用银杏叶片前后尿液内咖啡因5种主要代谢产物5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶(AFMU)、1-甲基尿酸(1U)、1-甲基黄嘌呤(1X)、1,7-二甲基尿酸(17U)和1,7-二甲基黄嘌呤(17X)的相对含量,采用(AFMU+1X+1U)/17U比值反映CYP1A2的活性,17U/(AFMU+1U+1X+17X+17U)反映CYP2A6在体内的活性,AFMU/(AFMU+1X+1U)反映NAT2的活性,1U/(1X+1U)反映XO的活性,对连续28天服用治疗剂量的银杏叶片对人肝脏药物代谢酶CYP1A2、CYP2A6、NAT2和XO活性的影响进行系统研究。
结果:RP-HPLC梯度洗脱直接进样法测定咖啡因5种主要代谢产物,具有样品前处理快捷有效,样品分析时间短,分离度和可靠性良好的特点,且可克服提取及分析过程对测定的干扰。服用银杏叶片前、服用银杏叶片28天,CYP1A2的平均活性分别为2.976±1.428,3.021±1.318,服药28天后比服药前升高1.51%,虽CYP1A2活性在服药后有所提高,但并无统计学差异;服用银杏叶片前、服用银杏叶片28天后,CYP2A6的平均活性分别为0.227±0.076,0.227±0.072,服药28天后与服药前相比基本没有变化,而且无统计学差异;服用银杏叶片前、服用银杏叶片28天后,NAT2的平均活性分别为0.447±0.172,0.391±0.147,服药28天后比服药前降低12.5%,,而且有明显统计学差异(P＜0.05);服用银杏叶片前、服用银杏叶片28天后,XO的平均活性分别为0.723±0.060,0.728±0.074,服药28天后比服药前升高0.69%,虽XO活性在服药后有所提高,但并无统计学差异。
结论:以咖啡因探针法测定正常人肝脏药物代谢酶CYP1A2、CYP2A6、NAT2和XO活性的RP-HPLC梯度洗脱直接进样法,为国内深入开展CYP1A2、CYP2A6、NAT2和XO四种酶的研究开拓了一种新方法;服用治疗剂量的银杏叶片对CYP1A2、CYP2A6和XO活性无明显影响,但是可以明显减低代谢酶NAT2的活性,说明银杏叶片不能通过药物代谢酶系统影响其他经CYP1A2、CYP2A6和XO酶代谢的药物临床疗效,但是可以影响经NAT2代谢的药物临床疗效。长期或者大剂量使用银杏叶片对CYP1A2、CYP2A6、NAT2和XO活性的影响值得进一步研究。
Objective:Cytochrome P450 enzyme 1A2(CYP1A2),Cytochrome P450 enzyme 2A6 (CYP2A6),N-acetyltransferase-2(NAT2),and xanthine oxidase(XO) play an important role while the drugs are metabolized and carcinogens are activated,their activation is closely related to curative effect or toxicity of a lot of drugs and susceptibility of some tumors,different active state of this enzymes must has certain influence on transformation of chemical material in vivo.To investigate the effect of ginkgo biloba tablets on CYP1A2,CYP2A6,NAT2 and XO activities in human and to forecast the drug-drug interaction of ginkgo biloba tablets,the activities of CYP1A2, CYP2A6,NAT2 and XO are assayed by metabolic probe which are contributed to predict medicine curative effect,prevent and mitigate medicine adverse effect, improve drug safety and instruct clinician to prescribe rationally.
Methods:Caffeine was used as a metabolic probe for CYP1A2,CYP2A6,NAT2 and XO,a HPLC method of metabolites of caffeine in the urine with direct injection was established for assuring the assay accuracy.The Shim-pack VP-COD column(4.6mm×150mm,5μm) and Shim-pack C18 pre-column were used.The mobile phase was acetonitrile and the gradient program was acetonitrile 2.5%to 10% in 0 to 24 min.The flow rate was 1.0mL.mim~(-1),and the column temperature was 25℃.The detective wavelength was at 280nm.In thirty volunteers,before and after ginkgo biloba tablets administration,urine samples were collected.The contents of five major metabolites of caffeine,5-acetylamino-6-formylamino-3-methyluracil(AFMU),1-methylxanthine(1X),1-methyluricacid(1U),1,7-dimethylurica cid(17U) and 1,7-dimethylxanthine(17X) in the urine were determined by RP-HPLC with direct injection method,and then the activity of CYP1A2,CYP2A6,NAT2 and XO were evaluated by respectively calculating the(AFMU+1X+1U)/17U, 17U/(AFMU+1U+1X+17X+17U),AFMU/(AFMU+1X+1U)and 1U/(1X+1U).The effect of therapeutic dose ginkgo biloba tablets administrated for 28 days were investigated simultaneously on CYP1A2,CYP2A6,NAT2 and XO respectively
Results:A new HPLC method of five metabolites of caffeine in the urine with direct injection was developed.The method is simple,rapid and accurate.It was found that the average activities of CYP1A2 were 2.976±1.428,3.021±1.318 before treatment,after taking medicine 28days respectively,There were no statistical significancet between before treatment and after taking medicine 28 days.It was found that the average activities of CYP2A6 were 0.227±0.076,0.227±0.072 before treatment,after taking medicine 28days respectively,There were no statistical significance between before treatment and after taking medicine 28 days.It was found that the average activities of NAT2 were0.447±0.172,0.391±0.147 before treatment,after taking medicine 28days respectively,There were statistical significance between before treatment and after taking medicine 28 days.It was found that the average activities of XO were 0.723±0.060,0.728±0.074 before treatment,after taking medicine 28days respectively,There were no statistical significance between before treatment and after taking medicine 28 days.
Conclusions:The method to measure simultaneously the activity of CYP1A2, CYP2A6,NAT2 and XO should contribute to simplifying and optimizing the caffeine drug metabolizing enzyme assays.Ginkgo biloba tablets have no influence on CYP1A2,CYP2A6and XO,so ginkgo biloba tablets do not modify the efficacy of drugs taken simultaneously which were metabolized by CYP1A2,CYP2A6 and XO.But ginkgo biloba tablets may modify the efficacy of drugs which metabolized by NAT2 taken simultaneously in slow acetylator.It is necessary to further study the effect of ginkgo biloba tablets administrated for long-term or in large dose on CYP1A2,CYP2A6,NAT2 and XO in human.
方法:以咖啡因作为药物代谢酶CYP1A2、CYP2A6、NAT2和XO的探针药物,为保证应用咖啡因代谢探针的正确性,采用岛津Shim-pack VP-ODS柱(4.6mm×150mm,5μm),岛津Shim-pack C18预柱,流动相为乙腈(A相),0.05%醋酸(B相),0-24min流动相B的比例从2.5%线性增加至10%,流速为1.0mL.min~(-1),柱温25℃,检测波长为280nm,建立了反相高效液相色谱(RP-HPLC)测定尿液中咖啡因代谢物的方法,采用该法测定30名受试者分别服用银杏叶片前后尿液内咖啡因5种主要代谢产物5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶(AFMU)、1-甲基尿酸(1U)、1-甲基黄嘌呤(1X)、1,7-二甲基尿酸(17U)和1,7-二甲基黄嘌呤(17X)的相对含量,采用(AFMU+1X+1U)/17U比值反映CYP1A2的活性,17U/(AFMU+1U+1X+17X+17U)反映CYP2A6在体内的活性,AFMU/(AFMU+1X+1U)反映NAT2的活性,1U/(1X+1U)反映XO的活性,对连续28天服用治疗剂量的银杏叶片对人肝脏药物代谢酶CYP1A2、CYP2A6、NAT2和XO活性的影响进行系统研究。
结果:RP-HPLC梯度洗脱直接进样法测定咖啡因5种主要代谢产物,具有样品前处理快捷有效,样品分析时间短,分离度和可靠性良好的特点,且可克服提取及分析过程对测定的干扰。服用银杏叶片前、服用银杏叶片28天,CYP1A2的平均活性分别为2.976±1.428,3.021±1.318,服药28天后比服药前升高1.51%,虽CYP1A2活性在服药后有所提高,但并无统计学差异;服用银杏叶片前、服用银杏叶片28天后,CYP2A6的平均活性分别为0.227±0.076,0.227±0.072,服药28天后与服药前相比基本没有变化,而且无统计学差异;服用银杏叶片前、服用银杏叶片28天后,NAT2的平均活性分别为0.447±0.172,0.391±0.147,服药28天后比服药前降低12.5%,,而且有明显统计学差异(P＜0.05);服用银杏叶片前、服用银杏叶片28天后,XO的平均活性分别为0.723±0.060,0.728±0.074,服药28天后比服药前升高0.69%,虽XO活性在服药后有所提高,但并无统计学差异。
结论:以咖啡因探针法测定正常人肝脏药物代谢酶CYP1A2、CYP2A6、NAT2和XO活性的RP-HPLC梯度洗脱直接进样法,为国内深入开展CYP1A2、CYP2A6、NAT2和XO四种酶的研究开拓了一种新方法;服用治疗剂量的银杏叶片对CYP1A2、CYP2A6和XO活性无明显影响,但是可以明显减低代谢酶NAT2的活性,说明银杏叶片不能通过药物代谢酶系统影响其他经CYP1A2、CYP2A6和XO酶代谢的药物临床疗效,但是可以影响经NAT2代谢的药物临床疗效。长期或者大剂量使用银杏叶片对CYP1A2、CYP2A6、NAT2和XO活性的影响值得进一步研究。
Objective:Cytochrome P450 enzyme 1A2(CYP1A2),Cytochrome P450 enzyme 2A6 (CYP2A6),N-acetyltransferase-2(NAT2),and xanthine oxidase(XO) play an important role while the drugs are metabolized and carcinogens are activated,their activation is closely related to curative effect or toxicity of a lot of drugs and susceptibility of some tumors,different active state of this enzymes must has certain influence on transformation of chemical material in vivo.To investigate the effect of ginkgo biloba tablets on CYP1A2,CYP2A6,NAT2 and XO activities in human and to forecast the drug-drug interaction of ginkgo biloba tablets,the activities of CYP1A2, CYP2A6,NAT2 and XO are assayed by metabolic probe which are contributed to predict medicine curative effect,prevent and mitigate medicine adverse effect, improve drug safety and instruct clinician to prescribe rationally.
Methods:Caffeine was used as a metabolic probe for CYP1A2,CYP2A6,NAT2 and XO,a HPLC method of metabolites of caffeine in the urine with direct injection was established for assuring the assay accuracy.The Shim-pack VP-COD column(4.6mm×150mm,5μm) and Shim-pack C18 pre-column were used.The mobile phase was acetonitrile and the gradient program was acetonitrile 2.5%to 10% in 0 to 24 min.The flow rate was 1.0mL.mim~(-1),and the column temperature was 25℃.The detective wavelength was at 280nm.In thirty volunteers,before and after ginkgo biloba tablets administration,urine samples were collected.The contents of five major metabolites of caffeine,5-acetylamino-6-formylamino-3-methyluracil(AFMU),1-methylxanthine(1X),1-methyluricacid(1U),1,7-dimethylurica cid(17U) and 1,7-dimethylxanthine(17X) in the urine were determined by RP-HPLC with direct injection method,and then the activity of CYP1A2,CYP2A6,NAT2 and XO were evaluated by respectively calculating the(AFMU+1X+1U)/17U, 17U/(AFMU+1U+1X+17X+17U),AFMU/(AFMU+1X+1U)and 1U/(1X+1U).The effect of therapeutic dose ginkgo biloba tablets administrated for 28 days were investigated simultaneously on CYP1A2,CYP2A6,NAT2 and XO respectively
Results:A new HPLC method of five metabolites of caffeine in the urine with direct injection was developed.The method is simple,rapid and accurate.It was found that the average activities of CYP1A2 were 2.976±1.428,3.021±1.318 before treatment,after taking medicine 28days respectively,There were no statistical significancet between before treatment and after taking medicine 28 days.It was found that the average activities of CYP2A6 were 0.227±0.076,0.227±0.072 before treatment,after taking medicine 28days respectively,There were no statistical significance between before treatment and after taking medicine 28 days.It was found that the average activities of NAT2 were0.447±0.172,0.391±0.147 before treatment,after taking medicine 28days respectively,There were statistical significance between before treatment and after taking medicine 28 days.It was found that the average activities of XO were 0.723±0.060,0.728±0.074 before treatment,after taking medicine 28days respectively,There were no statistical significance between before treatment and after taking medicine 28 days.
Conclusions:The method to measure simultaneously the activity of CYP1A2, CYP2A6,NAT2 and XO should contribute to simplifying and optimizing the caffeine drug metabolizing enzyme assays.Ginkgo biloba tablets have no influence on CYP1A2,CYP2A6and XO,so ginkgo biloba tablets do not modify the efficacy of drugs taken simultaneously which were metabolized by CYP1A2,CYP2A6 and XO.But ginkgo biloba tablets may modify the efficacy of drugs which metabolized by NAT2 taken simultaneously in slow acetylator.It is necessary to further study the effect of ginkgo biloba tablets administrated for long-term or in large dose on CYP1A2,CYP2A6,NAT2 and XO in human.
引文
[1]中国药典一部[M]北京:化学工业出版社,2005版:597-598
[2]付良青,吴德政.细胞色素P4502D6的研究进展[J].中国临床药理学杂志,2000,16(6):453-457
[3]Duvvuri S,Majumdar S,Mitra AK.Role of metabolism in ocular drug delivery [J].Curr Drug Metab.2004,5(6):507-515
[4]Kalow W,Tang BK.The use of caffeine for enzyme assays:a critical appraisal.[J].Clin Pharmacol Ther.1993,53(5):503-514
[5]黄林清,杨志勇.肝细胞色素P与药物代谢的研究进展[J].中国药房,2001,12(6):372-374
[6]Rendic S,Di Carlo FJ.Human cytochrome P450 enzymes:a status report summarizing their reactions,substrates,inducers,and inhibitors[J].Drug Metab Rev.1997,29(1-2):413-580
[7]张 铣,刘毓谷.毒理学[M].北京:北京医科大学中国协和医科大学联合出版社,1997:128-134
[8]Shimada T,Yamazaki H,Mimura M,etal.Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs,carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians[J].1994,270(1):414-423
[9]Distlerath LM,Reilly PE,Martin MV,etal.Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phena--cetin O-deethylation,two prototypes for genetic polymorphism in oxidative drug metabolism[J].J Biol Chem.1985,260(15):9057-9067
[10]Yoshimoto K,Echizen H,Chiba K,etal.Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP 1A2[J].Br J Clin Pharmacol.1995,39(4):421-431
[11]Daly AK,Cholerton S,Armstrong M,etal.Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility[J].Environ Health Perspect,1994,102(Suppl 9):55-61
[12]Jerling M,Lindstrom L,Bondesson U,etal.Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine:evidence from a therapeutic drug monit oring service[J].Ther Drug Monit.1994,16(4):368-374
[13]Heeringa M,Beurskens R,Schouten W,etal.Elevated plasma levels of clozapine after concomitant use of fluvoxamine[J].Pharm World Sci.1999,21(5):243-244
[14]Rasmussen BB,Nielsen TL,Brosen K.Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro[J].Pharmacol Toxicol.1998,83(6):240-245
[15]李菲,程泽能.与细胞色素P4501A2相关的药物相互作用[J].中国医院用药评价与分析,2002,2(2):114-115
[16]Oscarson M.Genetic polymorphisms in the cytochromeP4502A6(CYP2A6)gene:implications for interindividual differences in nicotine metabolism[J].Drug Metab Dispos.2001,29(2):91-95
[17]夏雪雁,彭仁绣.CYP2A6多态性对尼古丁代谢及烟草依赖行为的影响[J].药学学报,2004,39(9):758-763
[18]李 军,彭向前,张 鉴,等.以咖啡因为代谢探针测定细胞色素P450CYP2A6活性[J].药学学报,2006,41(3):282-284
[19]Hein DW.N-Acetyltransferase genetics and their role in predisposition to aromatic and heterocyclic amine-induced carcinogenesis[J].Toxicol Lett.2000,112-113:349-356.
[20]周宏灏.遗传药理学[M].北京:人民军医出版社,2003:100-106
[21]董瑞谦,郭瑞臣,曹宇梅,等.妊娠妇女乙酰化代谢表型的研究[J].中国临床药理学与治疗学,2003,8(3):304-307
[22]Asprodini EK,Zifa E,Papageorgiou I,etal.Determination of N-acetylation phenotyping in a Greek population using caffeine as a metabolic probe[J].Eur J Drug Metab Pharmacokinet,1998,23(4):501-506
[23]Guerciolini R,Szumlanski C,Weinshilboum RM.Human liver xanthine oxidase:nature and extent of individual variation[J].Clin Pharmacol Ther,1991,50(6):663-672.
[24]Saugstad OD.Role of xanthine oxidase and its inhibitor in hypoxia:reoxygenation injury.[J].Pediatrics,1996,98(1):103-107
[25]孔 悦,张 冰,刘小青,等.黄嘌呤氧化酶活性在高尿酸血症动物模型中的变化[J].北京中医药大学学报,2004,27(6):38-40
[26]王小京,李龙官.比色法测定黄嘌呤氧化酶[J].生物化学与生物物理进展,1996,(5):65-70
[27]Doehner W,Schoene N,Rauchhaus M,etal.Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure:results from 2 placebo-controlled studies[J].Circulation,2002,105(22):2619-24.
[28]Clancy RR,McGaurn SA,Goin JE,etal.Allopurinol neurocardiac protection trialin infants undergoing heart surgery using deep hypothermic circulatory arrest[J].Pediatrics,2001,108(1):61-70.
[29]孙忠实,朱珠.药物代谢性相互作用研究进展[J].药物不良反应杂志,2000,2(1):6-14
[30]李焕德,李坤艳.药物代谢性相互作用体外研究的重要性[J].中南药学,2005,3(3):179-181
[31]梁文权.生物药剂学与药物动力学[M].北京:人民卫生出版社,2000:110-117
[32]千叶宽,小林カオル.代谢过程[J].药局(日),1998,49(1):53-56
[33]Yuan R,Parmelee T,Balian JD,etal.In vitro metabolic interaction studies:experie--nce of the food and drug administration[J].Clin Pharmacol Ther.1999,66(1):9-15
[34]孙忠实.药物代谢与合理用药[J].中国药学杂志,2001,36(1):60-61
[35]娄小娥,章辉,吴美珍.药物基因组学与个体化用药[J].中国医院药学杂志,2002,55(5):304-305
[36]冷欣夫,邱星辉.细胞色素P450酶系的结构、功能与应用前景[M].北京:科学出版社,2001:186-204
[37]杨 静,彭仁琇,于皆平.18α- 甘草酸下调“胶原蛋白凝胶三明治”培养的大鼠肝细胞P450酶活性及mRNA表达[J].中国药理学与毒理学杂志,2001,15(2):155-158
[38]Trepanier EF,Nafziger AN,Keams GL,etal.Absence of effect of terbinafine on the activity of CYP 1A2,NAT-2,and xanthine oxidase[J].J Clin Pharmacol.1998,38 (5):424-428.
[39]周宏灏.遗传药理学[M].北京:人民军医出版社,2003:60-70
[40]卢建丰,易涛,曹晓梅,等.测定咖啡因代谢物评价N-乙酰转移酶、CYP1A2和黄嘌呤氧化酶活性[J].药学学报,1997,32(11):813-818
[41]Weimann A,Sabroe M,Poulsen HE.Measurement of caffeine and five of the major metabolites in urine by high-performance liquid chromatography/tandem mass spectrometry[J].J Mass Spectrom.2005,40(3):307-316
[42]Nyeki A,Biollaz J,Kesselring UW,etal.Extractionless method for the simultane--ous high-performance liquid chromatographic determination of urinary caffeine metabolites for N-acetyltransferase 2,cytochrome P450 1A2 and xanthine oxidase activity assessment[J].J Chromatogr B Biomed Sci Appl.2001,755(1-2):73-84
[43]Notarianni LJ,Oliver SE,Dobrocky P,etalCaffeine as a metabolic probe:a com--parison of the metabolic ratios used to assess CYP1A2 activity[J].Br J Clin Pharmacol,1995,39(1):65-69
[44]Bendriss EK,Markoglou N,Wainer IW.Liquid chromatographic method for the simultaneous determination of caffeine and fourteen caffeine metabolites in urine[J].J Chromatogr B,2000,746(2):331-338
[45]周权,姚彤炜,曾苏.代谢性的药物相互作用[J].中国临床药理学杂志,2001,17(3):313-315
[46]李军,彭向前,张鉴,等.HPLC直接进样测定咖啡因代谢物评价三种药物代谢酶活性[J].中国临床药理学与治疗学,2005,10(7):768-771
[47]周权,徐庆,寿军,等.植物药与西药的药动学相互作用[J].中国药学杂志,2004,39(12):884-887
[48]Umegaki K,Saito K,Kubota Y,et al.Ginkgo biloba Extract Markedly Induces Pentoxyresorufin O-Dealkylase Activity in Rats[J].Jpn J Pharmacol.2002,90(4):345
[49]Shinozuka K,Umegaki K,Kubota Y,et al.Feeding of Ginkgo biloba Extract(GBE) Enhances gene expression of hepatic cytochrome P-450 and attenuates the hypotensive effect of nicardipine in rats[J]Life Sci,2002,70(23):2783
[50]赵立子,马锦芳等.银杏叶提取物对细胞色素P450酶CYP1A2实验研究[J].中国临床药理学杂志,2005,21(2):122-125
[51]Sun H,Zuo Z,Yin OQ,et al."high-through put" cocktail method for screening the effect of herbal product on liver isoenzyme activities:experience with Ginkgo biloba [J].Clin Pharmacol Ther,2002,71(2):100
[52]薛洪源,侯艳宁,刘会臣.异烟肼与利福平合用致肝毒性增加机制的研究概况[J].中国现代应用药学,2002,19(6):463-466
[53]Dobrocky P,Bennett PN,Notarianni LJ.Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography[J].J Chromatogr.1994,652(1):104-108.
[54]刘丽娟,李军,郭瑞臣等.肝病患者药物代谢酶细胞色素P450酶1A2、多态性N-乙酰化酶、黄嘌呤氧化酶活性的变化[J].中国医院药学杂志,2000,20(4):212-213
[55]易涛,卢建丰.高效液相色谱法测定尿中咖啡因主要代谢物浓度[J].药学实践杂志,1997,15(2):94-99
[56]JamesEF,Reynolds.MartindaletheExtraPharmcpoeia 31 edition[M].London:the Royal pharmaceutical society's Publications Department,1996:1652-1653
[57]Kalow W,Tang BK.The use of caffeine for enzyme assays:a critical appraisal[J].Clin Pharmacol Ther.1993,53(5):503-514
[58]Sesardic D,Boobis AR,Edwards RJ,etal.A form of cytochrome P450 in man,orthologous to formed in the rat,catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking[J].Br J Clin Pharmacol.1988,26(4):363-372
[59]Fuhr U,Rost KL,Engelhardt R,etal.Evaluation of caffeine as a test drug for CYP1A2,NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations[J].Pharmacogenetics.1996,6(2):159-176
[60]Nyeki A,Buclin T,Biollaz J,etal.NAT2 and CYP1A2 phenotyping with caffeine:head-to-head comparison of AFMU vs.AAMU in the urine metabolite ratios[J].Br J Clin Pharmacol.2003,55(1):62-67
[61]Tsutsumi K,Kotegawa T,Matsuki S,etal.The effect of pregnancy on cytochrome P4501A2,xanthine oxidase,and N-acetyltransferase activities in humans[J].Clin Pharmacol Ther.2001,70(2):121-125
[62]Blanchard J,Sawers SJ.Relationship between urine flow rate and renal clearance of caffeine in man[J].J Clin Pharmacol.1983,23(4):134-138
[63]Sinues B,Saenz MA,Lanuza J,etal.Five caffeine metabolite ratios to measure tobacco-induced CYP1A2 activity and their relationships with urinary mutagenicity and urine flow.[J].Cancer Epidemiol Biomarkers Prey.1999,8(2):159-166
[64]Campbell ME,Spielberg SP,Kalow W.A urinary metabolite ratio that reflects systemic caffeine clearance[J].Clin Pharmacol Ther.1987,42(2):157-165
[65]Rost KL,Roots I.Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios:coincidence with plasma clearance and breath test.[J].Clin Pharmacol Ther.1994,55(4):402-411
[66]Schrenk D,Brockmeier D,Morike K,etal.A distribution study of CYP1A2phen-otypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers[J].Eur J Clin Pharmacol.1998,53(5):361-367
[67]Lampe JW,King IB,Li S,etal.Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans:changes in caffeine metab-olite ratios in response to controlled vegetable diets[J].Carcinogenesis.2000,21(6):1157-1162
[68]MilesJS,BickmoreW,BrookJD,etal.Close linkage of the human cytochrome P450IIA and P450IIB gene subfamilies:implications for the assignment of substrate specificity[J].Nucleic Acids Res,1989,17(8):2907-2917
[69]胡春松,朱文玲,程晓曙,等.检测CYP2A6基因多态性的PCR技术的基因型方法[J].中国药理学与毒理学杂志,2004,18(3):233-236
[70]Pelkonen O,Sotaniemi EA,Ahokas JT.Coumarin 7-hydroxylase activity in human liver microsomes.Properties of the enzyme and interspecies comparisons[J].BrJ Clin Pharmacol,1985,19(1):59-66
[71]Mwenifumbo JC,Myers MG,Wall TL,etal.Ethnic variation in CYP2A6~(*)7,CYP2A6~(*)8 and CYP2A6~(*) 10 as assessed with a novel haplotyping method [J].Pharmacogenet Genomics,2005,15(3):189-192
[72]Hickman D,Risch A,Buckle V,etal.Chromosomal localization of human genes for arylamine N-acetyltransferase.[J].Biochem J.1994,297(Pt 3):441-445
[73]郭瑞臣,崔唏,王本杰,等.国人乙酰化代谢表型测定研究(附203例报告)[J].山东医科大学学报,1997,35(4):344-347
[74]李军,彭向前,张鉴,等.咖啡因探针法测定正常人肝脏N-乙酰化转移酶活性[J].解放军药学学报,2005,21(6):407-409
[75]Nyeki A,Buclin T,Biollaz J,etal.NAT2 and CYP1A2 phenotyping with caffeine:head-to-head comparison of AFMU vs.AAMU in the urine metabolite ratios[J].Br J Clin Pharmacol.2003,55(1):62-67
[76]Nishino T,Nakanishi S,Okamoto K,etal.Conversion of xanthine dehydrogenase into oxidase and its role in reperfusion injury[J].Biochem Soc Trans,1997,25(3):783-786
[77]李东至,林其德,林建华妊高征患者血中黄嘌呤氧化酶和过氧化脂质水平的变化[J].中国病理生理杂志2002,18(7):773-777
[78]秦尤文.黄嘌呤脱氢酶研究进展[J].国外医学临床生物化学与检验学分册.2002,23(4):218-222
[79]Yokoyama Y,Beckman JS,Beckman TK,etal.Circulating xanthine oxidase:potential mediator of ischemic injury[J].Am J Physiol.1990,258(4 Pt 1):G564-G570
[80]刘春红,刘新郑.三种肝病患者血清黄嘌呤氧化酶的变化[J].河南医科大学学报,1998,33(1):81-82
[81]Guerciolini R,Szumlanski C,Weinshilboum RM.Human liver xanthine oxidase:nature and extent of individual variation[J].Clin Pharmacol Ther,1991,50(6):663-672
[82]Tang-Liu DD,Williams RL,Riegelman S.Disposition of caffeine and its metabolites in man[J].J Pharmacol Exp Ther,1983,224(1):180-185.
[83]Grant DM,Tang BK,Kalow W.Variability in caffeine metabolism[J].Clin Pharmacol Ther,1983,33(5):591-602.
[84]Tang BK,Kadar D,Qian L,etal.Caffeine as a metabolic probe:validation of its use for acetylator phenotyping[J].Clin Pharmacol Ther.,1991,49(6):648-657
[85]郭瑞臣,崔晞,徐祗顺,等.乙酰化代谢表型与膀胱癌关系的研究[J].中国临床药理学杂志,1997,13(3):139-144
[86]Tohda C,Sasaki M,Konemura T,etal.Axonal transport ofVR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity[J].J Neurochem,2001,76(6):1628-1635
[87]顾艳斐 张树才 赖百塘,等.CYP2A6基因多态性与肺癌易感性关系的研究[J].中国肺癌杂志,2005,8(4):297-299
[88]Camus AM,Geneste O,Honkakoski P,etal.High variability of Nitrosamine metabolism among individuals:role of cytochromes P4502A6 and 2El in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans[J].Mol Carcinog,1993,7(4):268-275
[89]Oscarson M,McLellan RA,Gullsten H,etal.Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population[J].FEBS Lett,1999,448(1):105-110
[90]Hengstler JG,Van der Burg B,Steinberg P,etal.Oesch F.Interspecies differences in cancer susceptibility and toxicity[J].Drug Metab Rev,1999,31(4):917-970
[91]Horai Y,Fujita K,Ishizaki T.Genetically determined N-acetylation and oxidation capacities in Japanese patients with non-occupational urinary bladder cancer[J].Eur J Clin Pharmacol,1989,37(6):581-587
[92]Morris ME,Griener JC,Msall ME.N-acetylator variability in Down's syndrome:characterization with caffeine[J].Clin Pharmacol Ther,1989,46(3):359-366
[93]Hein DW,Doll MA,Fretland AJ,etal.Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms[J].Cancer Epidemiol Biomarkers Prev,2000,9(1):29-42
[94]Biri H,Ozturk HS,Kacmaz M,etal.Activities of DNA turnover and free radical metabolizing enzymes in cancerous human prostate tissue[J].Cancer Invest,1999,17(5):314-319
[95]Ichinose M,Sugiura H,Yamagata S,etal.Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways[J]. Eur Respir J,2003 ,22(3): 457-461
[96]Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system[J]. Chem Biol Interact,2000,129(1 -2): 195-208
[97]Saugstad OD. Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury[J]. Pediatrics, 1996,98(1): 103-107.
[98] Hamada J,Greenberg JH,Croul S,etal. Effects of central inhibition of nitricoxide synthase on focal cerebral ischemia in rats [J]. J Cere Blood Flow Metab,1995, 5 (5) :779-786
[2]付良青,吴德政.细胞色素P4502D6的研究进展[J].中国临床药理学杂志,2000,16(6):453-457
[3]Duvvuri S,Majumdar S,Mitra AK.Role of metabolism in ocular drug delivery [J].Curr Drug Metab.2004,5(6):507-515
[4]Kalow W,Tang BK.The use of caffeine for enzyme assays:a critical appraisal.[J].Clin Pharmacol Ther.1993,53(5):503-514
[5]黄林清,杨志勇.肝细胞色素P与药物代谢的研究进展[J].中国药房,2001,12(6):372-374
[6]Rendic S,Di Carlo FJ.Human cytochrome P450 enzymes:a status report summarizing their reactions,substrates,inducers,and inhibitors[J].Drug Metab Rev.1997,29(1-2):413-580
[7]张 铣,刘毓谷.毒理学[M].北京:北京医科大学中国协和医科大学联合出版社,1997:128-134
[8]Shimada T,Yamazaki H,Mimura M,etal.Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs,carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians[J].1994,270(1):414-423
[9]Distlerath LM,Reilly PE,Martin MV,etal.Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phena--cetin O-deethylation,two prototypes for genetic polymorphism in oxidative drug metabolism[J].J Biol Chem.1985,260(15):9057-9067
[10]Yoshimoto K,Echizen H,Chiba K,etal.Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP 1A2[J].Br J Clin Pharmacol.1995,39(4):421-431
[11]Daly AK,Cholerton S,Armstrong M,etal.Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility[J].Environ Health Perspect,1994,102(Suppl 9):55-61
[12]Jerling M,Lindstrom L,Bondesson U,etal.Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine:evidence from a therapeutic drug monit oring service[J].Ther Drug Monit.1994,16(4):368-374
[13]Heeringa M,Beurskens R,Schouten W,etal.Elevated plasma levels of clozapine after concomitant use of fluvoxamine[J].Pharm World Sci.1999,21(5):243-244
[14]Rasmussen BB,Nielsen TL,Brosen K.Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro[J].Pharmacol Toxicol.1998,83(6):240-245
[15]李菲,程泽能.与细胞色素P4501A2相关的药物相互作用[J].中国医院用药评价与分析,2002,2(2):114-115
[16]Oscarson M.Genetic polymorphisms in the cytochromeP4502A6(CYP2A6)gene:implications for interindividual differences in nicotine metabolism[J].Drug Metab Dispos.2001,29(2):91-95
[17]夏雪雁,彭仁绣.CYP2A6多态性对尼古丁代谢及烟草依赖行为的影响[J].药学学报,2004,39(9):758-763
[18]李 军,彭向前,张 鉴,等.以咖啡因为代谢探针测定细胞色素P450CYP2A6活性[J].药学学报,2006,41(3):282-284
[19]Hein DW.N-Acetyltransferase genetics and their role in predisposition to aromatic and heterocyclic amine-induced carcinogenesis[J].Toxicol Lett.2000,112-113:349-356.
[20]周宏灏.遗传药理学[M].北京:人民军医出版社,2003:100-106
[21]董瑞谦,郭瑞臣,曹宇梅,等.妊娠妇女乙酰化代谢表型的研究[J].中国临床药理学与治疗学,2003,8(3):304-307
[22]Asprodini EK,Zifa E,Papageorgiou I,etal.Determination of N-acetylation phenotyping in a Greek population using caffeine as a metabolic probe[J].Eur J Drug Metab Pharmacokinet,1998,23(4):501-506
[23]Guerciolini R,Szumlanski C,Weinshilboum RM.Human liver xanthine oxidase:nature and extent of individual variation[J].Clin Pharmacol Ther,1991,50(6):663-672.
[24]Saugstad OD.Role of xanthine oxidase and its inhibitor in hypoxia:reoxygenation injury.[J].Pediatrics,1996,98(1):103-107
[25]孔 悦,张 冰,刘小青,等.黄嘌呤氧化酶活性在高尿酸血症动物模型中的变化[J].北京中医药大学学报,2004,27(6):38-40
[26]王小京,李龙官.比色法测定黄嘌呤氧化酶[J].生物化学与生物物理进展,1996,(5):65-70
[27]Doehner W,Schoene N,Rauchhaus M,etal.Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure:results from 2 placebo-controlled studies[J].Circulation,2002,105(22):2619-24.
[28]Clancy RR,McGaurn SA,Goin JE,etal.Allopurinol neurocardiac protection trialin infants undergoing heart surgery using deep hypothermic circulatory arrest[J].Pediatrics,2001,108(1):61-70.
[29]孙忠实,朱珠.药物代谢性相互作用研究进展[J].药物不良反应杂志,2000,2(1):6-14
[30]李焕德,李坤艳.药物代谢性相互作用体外研究的重要性[J].中南药学,2005,3(3):179-181
[31]梁文权.生物药剂学与药物动力学[M].北京:人民卫生出版社,2000:110-117
[32]千叶宽,小林カオル.代谢过程[J].药局(日),1998,49(1):53-56
[33]Yuan R,Parmelee T,Balian JD,etal.In vitro metabolic interaction studies:experie--nce of the food and drug administration[J].Clin Pharmacol Ther.1999,66(1):9-15
[34]孙忠实.药物代谢与合理用药[J].中国药学杂志,2001,36(1):60-61
[35]娄小娥,章辉,吴美珍.药物基因组学与个体化用药[J].中国医院药学杂志,2002,55(5):304-305
[36]冷欣夫,邱星辉.细胞色素P450酶系的结构、功能与应用前景[M].北京:科学出版社,2001:186-204
[37]杨 静,彭仁琇,于皆平.18α- 甘草酸下调“胶原蛋白凝胶三明治”培养的大鼠肝细胞P450酶活性及mRNA表达[J].中国药理学与毒理学杂志,2001,15(2):155-158
[38]Trepanier EF,Nafziger AN,Keams GL,etal.Absence of effect of terbinafine on the activity of CYP 1A2,NAT-2,and xanthine oxidase[J].J Clin Pharmacol.1998,38 (5):424-428.
[39]周宏灏.遗传药理学[M].北京:人民军医出版社,2003:60-70
[40]卢建丰,易涛,曹晓梅,等.测定咖啡因代谢物评价N-乙酰转移酶、CYP1A2和黄嘌呤氧化酶活性[J].药学学报,1997,32(11):813-818
[41]Weimann A,Sabroe M,Poulsen HE.Measurement of caffeine and five of the major metabolites in urine by high-performance liquid chromatography/tandem mass spectrometry[J].J Mass Spectrom.2005,40(3):307-316
[42]Nyeki A,Biollaz J,Kesselring UW,etal.Extractionless method for the simultane--ous high-performance liquid chromatographic determination of urinary caffeine metabolites for N-acetyltransferase 2,cytochrome P450 1A2 and xanthine oxidase activity assessment[J].J Chromatogr B Biomed Sci Appl.2001,755(1-2):73-84
[43]Notarianni LJ,Oliver SE,Dobrocky P,etalCaffeine as a metabolic probe:a com--parison of the metabolic ratios used to assess CYP1A2 activity[J].Br J Clin Pharmacol,1995,39(1):65-69
[44]Bendriss EK,Markoglou N,Wainer IW.Liquid chromatographic method for the simultaneous determination of caffeine and fourteen caffeine metabolites in urine[J].J Chromatogr B,2000,746(2):331-338
[45]周权,姚彤炜,曾苏.代谢性的药物相互作用[J].中国临床药理学杂志,2001,17(3):313-315
[46]李军,彭向前,张鉴,等.HPLC直接进样测定咖啡因代谢物评价三种药物代谢酶活性[J].中国临床药理学与治疗学,2005,10(7):768-771
[47]周权,徐庆,寿军,等.植物药与西药的药动学相互作用[J].中国药学杂志,2004,39(12):884-887
[48]Umegaki K,Saito K,Kubota Y,et al.Ginkgo biloba Extract Markedly Induces Pentoxyresorufin O-Dealkylase Activity in Rats[J].Jpn J Pharmacol.2002,90(4):345
[49]Shinozuka K,Umegaki K,Kubota Y,et al.Feeding of Ginkgo biloba Extract(GBE) Enhances gene expression of hepatic cytochrome P-450 and attenuates the hypotensive effect of nicardipine in rats[J]Life Sci,2002,70(23):2783
[50]赵立子,马锦芳等.银杏叶提取物对细胞色素P450酶CYP1A2实验研究[J].中国临床药理学杂志,2005,21(2):122-125
[51]Sun H,Zuo Z,Yin OQ,et al."high-through put" cocktail method for screening the effect of herbal product on liver isoenzyme activities:experience with Ginkgo biloba [J].Clin Pharmacol Ther,2002,71(2):100
[52]薛洪源,侯艳宁,刘会臣.异烟肼与利福平合用致肝毒性增加机制的研究概况[J].中国现代应用药学,2002,19(6):463-466
[53]Dobrocky P,Bennett PN,Notarianni LJ.Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography[J].J Chromatogr.1994,652(1):104-108.
[54]刘丽娟,李军,郭瑞臣等.肝病患者药物代谢酶细胞色素P450酶1A2、多态性N-乙酰化酶、黄嘌呤氧化酶活性的变化[J].中国医院药学杂志,2000,20(4):212-213
[55]易涛,卢建丰.高效液相色谱法测定尿中咖啡因主要代谢物浓度[J].药学实践杂志,1997,15(2):94-99
[56]JamesEF,Reynolds.MartindaletheExtraPharmcpoeia 31 edition[M].London:the Royal pharmaceutical society's Publications Department,1996:1652-1653
[57]Kalow W,Tang BK.The use of caffeine for enzyme assays:a critical appraisal[J].Clin Pharmacol Ther.1993,53(5):503-514
[58]Sesardic D,Boobis AR,Edwards RJ,etal.A form of cytochrome P450 in man,orthologous to formed in the rat,catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking[J].Br J Clin Pharmacol.1988,26(4):363-372
[59]Fuhr U,Rost KL,Engelhardt R,etal.Evaluation of caffeine as a test drug for CYP1A2,NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations[J].Pharmacogenetics.1996,6(2):159-176
[60]Nyeki A,Buclin T,Biollaz J,etal.NAT2 and CYP1A2 phenotyping with caffeine:head-to-head comparison of AFMU vs.AAMU in the urine metabolite ratios[J].Br J Clin Pharmacol.2003,55(1):62-67
[61]Tsutsumi K,Kotegawa T,Matsuki S,etal.The effect of pregnancy on cytochrome P4501A2,xanthine oxidase,and N-acetyltransferase activities in humans[J].Clin Pharmacol Ther.2001,70(2):121-125
[62]Blanchard J,Sawers SJ.Relationship between urine flow rate and renal clearance of caffeine in man[J].J Clin Pharmacol.1983,23(4):134-138
[63]Sinues B,Saenz MA,Lanuza J,etal.Five caffeine metabolite ratios to measure tobacco-induced CYP1A2 activity and their relationships with urinary mutagenicity and urine flow.[J].Cancer Epidemiol Biomarkers Prey.1999,8(2):159-166
[64]Campbell ME,Spielberg SP,Kalow W.A urinary metabolite ratio that reflects systemic caffeine clearance[J].Clin Pharmacol Ther.1987,42(2):157-165
[65]Rost KL,Roots I.Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios:coincidence with plasma clearance and breath test.[J].Clin Pharmacol Ther.1994,55(4):402-411
[66]Schrenk D,Brockmeier D,Morike K,etal.A distribution study of CYP1A2phen-otypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers[J].Eur J Clin Pharmacol.1998,53(5):361-367
[67]Lampe JW,King IB,Li S,etal.Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans:changes in caffeine metab-olite ratios in response to controlled vegetable diets[J].Carcinogenesis.2000,21(6):1157-1162
[68]MilesJS,BickmoreW,BrookJD,etal.Close linkage of the human cytochrome P450IIA and P450IIB gene subfamilies:implications for the assignment of substrate specificity[J].Nucleic Acids Res,1989,17(8):2907-2917
[69]胡春松,朱文玲,程晓曙,等.检测CYP2A6基因多态性的PCR技术的基因型方法[J].中国药理学与毒理学杂志,2004,18(3):233-236
[70]Pelkonen O,Sotaniemi EA,Ahokas JT.Coumarin 7-hydroxylase activity in human liver microsomes.Properties of the enzyme and interspecies comparisons[J].BrJ Clin Pharmacol,1985,19(1):59-66
[71]Mwenifumbo JC,Myers MG,Wall TL,etal.Ethnic variation in CYP2A6~(*)7,CYP2A6~(*)8 and CYP2A6~(*) 10 as assessed with a novel haplotyping method [J].Pharmacogenet Genomics,2005,15(3):189-192
[72]Hickman D,Risch A,Buckle V,etal.Chromosomal localization of human genes for arylamine N-acetyltransferase.[J].Biochem J.1994,297(Pt 3):441-445
[73]郭瑞臣,崔唏,王本杰,等.国人乙酰化代谢表型测定研究(附203例报告)[J].山东医科大学学报,1997,35(4):344-347
[74]李军,彭向前,张鉴,等.咖啡因探针法测定正常人肝脏N-乙酰化转移酶活性[J].解放军药学学报,2005,21(6):407-409
[75]Nyeki A,Buclin T,Biollaz J,etal.NAT2 and CYP1A2 phenotyping with caffeine:head-to-head comparison of AFMU vs.AAMU in the urine metabolite ratios[J].Br J Clin Pharmacol.2003,55(1):62-67
[76]Nishino T,Nakanishi S,Okamoto K,etal.Conversion of xanthine dehydrogenase into oxidase and its role in reperfusion injury[J].Biochem Soc Trans,1997,25(3):783-786
[77]李东至,林其德,林建华妊高征患者血中黄嘌呤氧化酶和过氧化脂质水平的变化[J].中国病理生理杂志2002,18(7):773-777
[78]秦尤文.黄嘌呤脱氢酶研究进展[J].国外医学临床生物化学与检验学分册.2002,23(4):218-222
[79]Yokoyama Y,Beckman JS,Beckman TK,etal.Circulating xanthine oxidase:potential mediator of ischemic injury[J].Am J Physiol.1990,258(4 Pt 1):G564-G570
[80]刘春红,刘新郑.三种肝病患者血清黄嘌呤氧化酶的变化[J].河南医科大学学报,1998,33(1):81-82
[81]Guerciolini R,Szumlanski C,Weinshilboum RM.Human liver xanthine oxidase:nature and extent of individual variation[J].Clin Pharmacol Ther,1991,50(6):663-672
[82]Tang-Liu DD,Williams RL,Riegelman S.Disposition of caffeine and its metabolites in man[J].J Pharmacol Exp Ther,1983,224(1):180-185.
[83]Grant DM,Tang BK,Kalow W.Variability in caffeine metabolism[J].Clin Pharmacol Ther,1983,33(5):591-602.
[84]Tang BK,Kadar D,Qian L,etal.Caffeine as a metabolic probe:validation of its use for acetylator phenotyping[J].Clin Pharmacol Ther.,1991,49(6):648-657
[85]郭瑞臣,崔晞,徐祗顺,等.乙酰化代谢表型与膀胱癌关系的研究[J].中国临床药理学杂志,1997,13(3):139-144
[86]Tohda C,Sasaki M,Konemura T,etal.Axonal transport ofVR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity[J].J Neurochem,2001,76(6):1628-1635
[87]顾艳斐 张树才 赖百塘,等.CYP2A6基因多态性与肺癌易感性关系的研究[J].中国肺癌杂志,2005,8(4):297-299
[88]Camus AM,Geneste O,Honkakoski P,etal.High variability of Nitrosamine metabolism among individuals:role of cytochromes P4502A6 and 2El in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans[J].Mol Carcinog,1993,7(4):268-275
[89]Oscarson M,McLellan RA,Gullsten H,etal.Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population[J].FEBS Lett,1999,448(1):105-110
[90]Hengstler JG,Van der Burg B,Steinberg P,etal.Oesch F.Interspecies differences in cancer susceptibility and toxicity[J].Drug Metab Rev,1999,31(4):917-970
[91]Horai Y,Fujita K,Ishizaki T.Genetically determined N-acetylation and oxidation capacities in Japanese patients with non-occupational urinary bladder cancer[J].Eur J Clin Pharmacol,1989,37(6):581-587
[92]Morris ME,Griener JC,Msall ME.N-acetylator variability in Down's syndrome:characterization with caffeine[J].Clin Pharmacol Ther,1989,46(3):359-366
[93]Hein DW,Doll MA,Fretland AJ,etal.Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms[J].Cancer Epidemiol Biomarkers Prev,2000,9(1):29-42
[94]Biri H,Ozturk HS,Kacmaz M,etal.Activities of DNA turnover and free radical metabolizing enzymes in cancerous human prostate tissue[J].Cancer Invest,1999,17(5):314-319
[95]Ichinose M,Sugiura H,Yamagata S,etal.Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways[J]. Eur Respir J,2003 ,22(3): 457-461
[96]Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system[J]. Chem Biol Interact,2000,129(1 -2): 195-208
[97]Saugstad OD. Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury[J]. Pediatrics, 1996,98(1): 103-107.
[98] Hamada J,Greenberg JH,Croul S,etal. Effects of central inhibition of nitricoxide synthase on focal cerebral ischemia in rats [J]. J Cere Blood Flow Metab,1995, 5 (5) :779-786