咖啡因代谢探针研究乙酰化代谢表型与膀胱癌关系

摘要/Abstract

摘要： 目的以咖啡因为代谢探针,研究膀胱癌发生发展的N-乙酰化代谢表型分布的统计学相关性。方法根据人尿液中咖啡因代谢物5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶(AFMU)和甲磺嘌呤1X)的峰高比值绘制概率分布直方图和概率单位图,寻找区分快慢乙酰化代谢表型的截点,确定人的乙酰化代谢表型分布。结果健康志愿者和膀胱癌患者概率分布直方图和概率单位图呈明显多态性,截点为1.10,即大于1.10为快乙酰化代谢表型,小于1.10为慢乙酰化代谢表型。健康志愿者中快、慢人乙酰化表型分别为149例(73.7%)和54例(26.3%)。膀胱癌患者分别为36例(53.7%)和31例(46.3),两者存在显著统计学差异(P<0.01)。志愿者和膀胱癌患者基因频率分别为0.51和0.68,优势比为2.376(95%可信区间为1.3513和4.1776)。结论中国人乙酰化代谢表型分布呈多型性。慢乙酰化代谢表型个体可能为膀胱癌多发和易感人群。

关键词: 乙酰化代谢多态性, 膀胱癌, 咖啡因, 表型

Abstract: Aim Acetylator status of 203 healthy controls and 67 patients with bladder cancer was observed.Methods All the subject s w ere N-acetylate-phenotyped with caffeine asametabolic probe drug.Urine samples were collected 2 hours after a cuPof 140mg-caffeine-spiked coffee was taken under fasting condition in the morning.The caffeine metabolites,5-acetylamino-6-formylamino-1-me thyluracil(AFMU) and 1-methy lxanthine (1X)were analysed by High Performance Liquid Chromatog raphy(HPLC).The frequence histogram and probit plot were constructed to select the antimode which was used to assess slow and fast acetylator statusboth in healthy controls and patients with bladder cancer.Results The peak hight ratios (PHR)of AFMU/1X were from 0.06 to 6.5 for healthy voluteers and 0.1 to 6.31 for patients with bladder cancer.Of the 203 healthy controls involved in this study 73.7%(149/203)had the AFMU/1X>1.10,and were classified as fast acetylators,and 26.3%(54/203)as slow acetylators,while 53.7%(36/67)were fast acetylators and 46.3%(31/67)were slow acetylators in patients with bladder cancer.The oddsratio was 2.376,and the genefreqency for healthy controls and for patients with urinary bladder cancer was 0.51 and 0.68 respectively.Conclusion The acetylator status of Chinese population is polymorphic and completely in concordance with that determined by dapsone,isoniazid or sulfamethazine methords as previously reported.Slow acetylators might be susceptible to urinary bladder cancer.

Key words: N-acetylation, polymorphism, bladder cancer, caffeine

中图分类号:

R965

郭瑞臣, 崔唏, 徐祗顺, 王本杰, 李朝武. 咖啡因代谢探针研究乙酰化代谢表型与膀胱癌关系[J]. 中国临床药理学与治疗学, 1998, 3(4): 250-255.

GUO Rui-Chen, CUI Xi, XU Zhi-Shun, WANG Ben-Jie, LI Chao-Wu. Relationship between bladder cancer and slow N-acetylators phenotyped with caffeine as a probe drug in Chinese population[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 1998, 3(4): 250-255.

参考文献

1 Guo RC,Thormann W.Ace tylator pheno typ-ing viaanalysis of four caffeine metabolites in hu-man urine by micellare lectrokinetic capillary chromatog raphy with multiw avelength detection.Elec trophoresis,1993;14:547
2 Kadluber FF.Po rlymorphism for aroma tic amine metabolism in humans:relevance for human car cinogens.Envir Health perspect,1992;98:69
3 Lunde PKM,Frislid K,Hasteen V.Disease and acetylation prolymorphism.Clin Pharmacokine t,1977;2:182
4 Bing-kouTang,Kadar D,Qian Li,et al.Caffeine as a me tabolicprobe:Validation of its use foracetylator pheno typing.Clin pharmacol Ther,1991;40(6):649
5 David WJ,Clark.Genetically determined Vari-ability in acety lation and oxidation:Ther apeutic implications,drugs,1985;29:342
6 Da vid A,Evans P.N-acety ltransfer ase.Clin Pharmacol Ther,1989;42:157
7 Guo RC,Thormann W,Lauteerberg BH.The Relationship between high incidence of adverse dapsone reactions in AIDs patients and slow acetylato rpheno type or low plasma/lympho-cyteglutathione level of these patients.Chinese Medical Journal (English edition ),1996;109(12):9:33
8 Dajani RM,Kayyali S,Saheb SE,et al.A study on the physiological disposition of acetophenetidin by the diabetic man.Comp Gen Pharmacol,1974;5:1
9 Songqi J,Aiping Z,Min L.The study of rela-tionship between scety lation polymo phism and bladder cancer.Chinese Occupational Medicine,1994;21(2):2
10 Low er BM,Nilsson T,Nelson C E,et al.N-a cetyl-transtera sepheno type and risk in urinary bladder cancer:a pproaches in mole cularepidemio logy,preliminary re sults in Sweden and Demark.Envir Health Pe rspect,1979;29:71
11 Case RAM,Hosker ME,McDonald DB,e t al.Tumors of the urinary bladder in workman engaged in the manufacture and use of certain,dy estuff in termediates in the British Chemical Industry.Role of mailine,benzidine alphanaphthy lamine,and beta-naphthy lamin.Br J Ind M ed,1954;11:75
12 Rodomski JL,Brill E.Bladder cancer induction by a romatics amines:Ro le of N-hydroxy metabolites.Science,1979;167:992
13 Low e r GM.Concepts in causality:Chemically induced human urinary bladder cancer.Cancer,1982;49:1056
14 Risch A,Wallace DW,Bat hers S,et al.Slow N-acety lationgeno type is a susceptibility factor in occupational and smoking related bladder cancer.Hum Mol Genet,1995;4(2):231
15 Hanke J,Krajewska B.Acetylation phenotype and bladder cancer.J Occup Med,1991;32:917
16 Weber WW,Hein DW,Litwin A,et al.Relationship of acetylator status to isoniazid toxicity,lupusery thematosus and bladder cancer.FAS EB J,1983;42:3086
17 Richard B,Hay es,wenfang B,et al.N-acetylation phenotype and genotype and risk of bladder cancer in benzidine-exposed works.Carcino genesis,1993;14(4):675
18 Horai Y,Fujjita K,I shizaki T.Genetically determined N-acetylation and oxidation capacities in Japanese patients with nonoccupational urinary bladder cancer.Eur J Clin Pharmacol,1989;37:581

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