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研究生:陳維邦
研究生(外文):Wei-Bang Chen
論文名稱:甲基安非他命之基因毒性研究
論文名稱(外文):Studies on the Genetic Toxicity of Methamphetamine
指導教授:李志恆李志恆引用關係
指導教授(外文):Jih-Heng Li
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:遺傳學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:71
中文關鍵詞:甲基安非他命基因毒性自由基hgprt基因突變分析法微核試驗染色體變異分析中國倉鼠卵巢細胞
外文關鍵詞:methamphetaminegenetic toxicityfree radicalhgprt mutation assaymicronucleichromosome aberrationCHO-K1
相關次數:
  • 被引用被引用:1
  • 點閱點閱:237
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  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
甲基安非他命屬於中樞神經興奮劑的一種,可以增加生理及神智的清醒,因此在校園、軍中、特殊場所及過度耗費體力的族群中都發生了嚴重的流行。長期的使用會造成心理的依賴性及生理的耐受性而成癮,引起不少的社會問題。所以甲基安非他命是否具有基因毒性,不容我們忽視。因此,我們選擇下列常用的基因毒性分析法來評估甲基安非他命的基因毒性。測試的方式包括:hgprt基因突變分析法、微核試驗以及染色體變異分析試驗。實驗結果顯示,分別以1 mM、2 mM、3 mM、4 mM四種濃度的右旋甲基安非他命處理中國倉鼠卵巢細胞(CHO-K1)二十四小時後,均會造成致突變率、微核細胞數目及染色體變異細胞數目的上升,這說明了右旋甲基安非他命確實會造成去氧核醣核酸的傷害而具有基因毒性。此外,在不具有多巴氨系統的中國倉鼠卵巢細胞中,我們利用DCF assay觀察到甲基安非他命會引起細胞內的自由基含量增加。而除了mannitol之外的多種自由基清除劑,如:GSH、SOD、Catalase均可抑制由右旋甲基安非他命引起的微核細胞數目而提供保護作用。這說明了右旋甲基安非他命可能是藉由過氧化自由基造成基因毒性的機制。
Methampetamine has long been a drug of abuse and become a serious problem in this country recently,. Its high abuse liability is evidenced by the fact that methamphetamine is self administered by experimental animals and abused by human. The genetic toxicity of d-methamphetamine was evaluated by the following approaches: (1) mammalian cell hgprt mutation assay; (2) micronuclei and (3) chromosome aberration assay. CHO-K1 cells were treated with various doses of d-methamphetamine (1 mM, 2 mM, 3 mM and 4 mM) for 24 hours. These results showed that d-methamphetamine significantly increased the hgprt mutagenicity, induced micronucleus formation and increased chromosomal aberrations in CHO-K1 cells. This study indicates d-methamphetamine is capable of inducing genotoxicity. We also observed that exposure to d-methamphetamine increased the free radical production in CHO-K1 cells, which can not be stimulated by d-methamphetamine to release dopamine. However, except mannitol, several free radical scavengers, including GSH, SOD and catalase, inhibited the d-methamphetamine-induced micronucleus formation. These results indicated that d-methamphetamine might induce genotoxicity via superoxide radicals.
目     錄
中文摘要 1
英文摘要 2
緒論 3
《壹》甲基安非他命的起源 3
《貳》甲基安非他命的化學結構及特性 10
《參》甲基安非他命在人體中的代謝作用 12
《肆》甲基安非他命的藥物動力學與藥理作用 13
《伍》甲基安非他命的神經毒性與臨床症狀 15
《陸》研究動機及研究策略 19
材料與方法 26
《壹》試藥與溶液 26
《貳》實驗方法 29
結果 33
《壹》甲基安非他命之基因毒性分析 33
《貳》甲基安非他命基因毒性機制之探討 36
討論 39
圖表 47
參考文獻 58
附錄 67
參考文獻
1. 行政院衛生署藥物濫用防治宣導教育手冊,台灣台北。55~71, 1997.
2. 林信男 藥物濫用:橘井文化事業股份有限公司,台灣台北。16~24, 1994.
3. 台北榮民總醫院毒藥物季刊,台灣台北。1~8, 1990 Nov.
4. 林杰樑 如何預防您的孩子染上毒癮:健康世界雜誌社,台灣台北。17~31, 1991.
5. 行政院衛生署藥物食品檢驗局濫用藥物彙編-毒性、代謝與檢驗,台灣台北。45~67, 1996.
6. 何瑞麟譯 實用精神藥物學:合記圖書出版社,台灣台北。409~419, 1985.
7. 高承源 安非他命類之基因毒性探討:國立陽明大學遺傳所碩士論文。19~22, 1996.
8. Beebe, D.K. and Walley, E. Smokable Methamphetamine (‘Ice’): An Old Drug in a Different Form. American Family Physician. 27: 449~453, 1995.
9. Piness, G., Miller, H. and Alles, G.A. Clinical observations on phenylaminoethanol sulphate. J. Am. Med. Assoc. 94: 790~791, 1930.
10. Ersner, J.S. The treatment of obesity due to dietary indiscretion (overeating) with benzedrine sulphate. Endocrinology. 27: 776~780, 1940.
11. Gillman, A.G., Goodman, L.S., Rall, T.W. and Murad, F. Goodman and Gilman’s The pharmacological Basis of Therapeutics. 8th Ed.: Macmillan Publishing Co., New York, U.S.A., 210~218, 1990.
12. Youngs, D. and Scoville, W.B. Paranoid psychosis in narcolepsy and the possible dangers of benzedrine treatment. Med. Clin. North. Am. 22: 637~646, 1938.
13. Connell, P.H. Amphetamine Psycosis.: Oxford University Press. London., 1958.
14. Derlet, R.W. and Heischober B. Methamphetamine Stimulant of the 1990’s? West J. Med. 153: 625~628, 1990.
15. Kunkel, D.B. Amphetamines and amphetamine-like drugs. In: Tintinalli, J.E., Krome, R.L. and Ruiz, E. Emergency medicine: a comprehensive study guide. 2nd Ed.: McGraw-Hill, New York, U.S.A., 713~714, 1988.
16. Ellenhorn, M.J. Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd Ed.: Williams & Wilkins, Maryland, U.S.A., 340~355, 1997.
17. Zarcone, V. Narcolepsy. New England Journal of Medicine. 288(22):1156~1166, 1973.
18. Nahmias, J. and Karetzky, M.S. Current concepts in narcolepsy. New Jersey Medicine. 86(8):617~622, 1989.
19. Moffat, A.C., Jackson, J.V., Moss, M.S., Widdop, B. and Greenfield, E.S. Clarke’s isolation and identification of drugs in pharmaceuticals, body fluids, and post-mortem material. 2nd Ed. : Pharmaceutical Press, London, 349~350,763~764, 1997.
20. Fitzgerald, R.L., Ramos, J.M. Jr., Bogema, S.C. and Poklis, A. Resolution of methamphetamine stereoisomers in urine drug testing: urinary excretion of R(-)-methamphetamine following use of nasal inhalers. Journal of Analytical Toxicology. 12(5):255~259, 1988.
21. Ferris, R.M., Tang, F.L. and Maxwell, R.A. A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta. Journal of Pharmacology & Experimental Therapeutics. 181(3):407~16, 1972.
22. Snyder, S.H. Catecholamines in the brain as mediators of amphetamine psychosis. Archives of General Psychiatry. 27(2):169~79, 1972.
23. Dring, L.G., Smith, R.L. and Williams, R.T. The fate of amphetamine in man and other mammals. Journal of Pharmacy & Pharmacology. 18(6):402~404, 1966.
24. Beckett, A.H. and Rowland, M. Urinary excretion kinetics of amphetamine in man. Journal of Pharmacy & Pharmacology. 17(10):628~639, 1965.
25. Kuhn, D.M., Appel, J.B. and Greenberg, I. An analysis of some discriminative properties of d-amphetamine. Psychopharmacologia. 39(1):57~66, 1974.
26. Ross, S.B. and Renyl, A.L. Blocking action of sympathomimetic amines on the uptake of tritiated noradrenaline by mouse cerebral cortex tissues in vitro. Acta. Pharmacol. Toxicol. 21: 226~239, 1964.
27. Mantle, T.J., Tipton, K.F. and Garrett, N.J. Inhibition of monoamine oxidase by amphetamine and related compounds. Biochemical Pharmacology. 25(18):2073~7, 1976.
28. Baldessarini, R.J. Symposium: behavior modification by drugs. I. Pharmacology of the amphetamines. Pediatrics. 49(5):694~701, 1972.
29. Seiden, L.S., Fischman, M.W. and Schuster, C.R. Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys. Drug & Alcohol Dependence. 1: 215~219, 1976.
30. Hotchkiss, A., and Gibb, J.W. Blockade of methamphetamine-induced depression of tyrosine hydroxylase by GABA transaminase inhibitors. European Journal of Pharmacology. 66: 201~205, 1980.
31. Hotchkiss, A.J., and Gibb, J.W. Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. Journal of Pharmacology & Experimental Therapeutics. 214: 257~262, 1980.
32. Wagner, G.C., Ricaurte, G.A., Seiden, L.S., Schuster, C.R., Miller, R.J. and Westley, J. Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Research. 181: 151~160, 1980.
33. Steranka, L.R. and Sanders-Bush, E. Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice. European Journal of Pharmacology. 65: 439~443, 1980.
34. Wagner, G.C., Ricaurte, G.A.,. Johanson, C.E., Schuster, C.R. and Seiden, L.S. Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate. Neurology. 30: 547~550, 1980.
35. Wagner, G.C., Seiden, L.S. and Schuster, C.R. Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs. Drug & Alcohol Dependence. 4: 435-438, 1979.
36. Levine, M.S., Hull, C.D., Garcia-Rill, E., Erinoff L., Buchwald, N.A. and Heller A. Long-term decreases in spontaneous firing of caudate neurons induced by amphetamine in cats. Brain Research. 194: 263~268, 1980.
37. Nwanze, E. and Johsson, G. Amphetamine toxicity on dopamine nerver terminals in the caudate nucleus of mice. Neuroscience Letter. 26: 163~168, 1980.
38. Woolverton, W.L., Ricaurte, G.A., Forno, L.S. and Seiden, L.S. Long-term effects of chronic methamphetamine administration in rhesus monkeys. Brain Research. 486: 73~78, 1989.
39. Seiden, L.S. and Ricaurte, G. Neurotoxicity of methamphetamine and related drugs. In: Meltzer, H.Y. Psychopharmacology: The Third Generation of Progress.: Raven, New York, U.S.A., 359~365, 1987.
40. Seiden, L.S. Fischman, M.W. and Schuster, C.R. Changes in brain catecholamines induced by long-term methamphetamine administration in rhesus monkeys. In: Ellinwood, E.H. Cocaine and Other Stimulants.: Plenum, New York, U.S.A., 179~185, 1977.
41. Axt, K.J., Commins, D.L., Vosmer, G. and Seiden, L.S. Alpha-Methyl-p-tyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation. Brain Research. 515: 269~276, 1990.
42. O''Hearn, E., Battaglia, G., DeSouza, E.B., Kuhar, M.J. and Molliver, M.E. Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. Journal of Neuroscience. 8: 2788~2803, 1988.
43. Ryan, L.J., Linder, J.C., Martone, M.E. and Groves, P.M. Histological and ultrastructural evidence that D-amphetamine causes degeneration in neostriatum and frontal cortex of rats. Brain Research. 518: 67~77, 1990.
44. Espelin, D.E. and Done, A.K. Amphetamine poisoning. Effectiveness of chlorpromazine. New England Journal of Medicine. 278: 1361~1365, 1968.
45. Mack, R.B. The iceman cometh and killeth: smokable methamphetamine. North Carolina Medical Journal. 51: 276~278, 1990.
46. Call, T.D., Hartneck, J., Dickinson, W.A., Hartman, C.W. and Bartel, A.G. Acute cardiomyopathy secondary to intravenous amphetamine abuse. Annals of Internal Medicine. 97: 559~560, 1982.
47. Rothrock, J.F., Rubenstein, R. and Lyden, P.D. Ischemic stroke associated with methamphetamine inhalation. Neurology. 38: 589~592, 1988.
48. Salanova, V. and Taubner, R. Intracerebral haemorrhage and vasculitis secondary to amphetamine use. Postgraduate Medical Journal. 60: 429~430, 1984.
49. Weiss, S.R., Raskind, R., Morganstern, N.L., Pytlyk, P.J. and Baiz, T.C. Intracerebral and subarachnoid hemorrhage following use of methamphetamine ("speed"). International Surgery. 53: 123~127, 1970.
50. Hong, R., Matsuyama, E. and Nur, K. Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA. 265: 1152-1154, 1991.
51. Nestor, T.A., Tamamoto, W.I., Kam, T.H. and Schultz, T. Crystal methamphetamine-induced acute pulmonary edema: a case report. Hawaii Medical Journal. 48: 457-458, 460, 1989
52. Jacobs, L.J. Reversible dilated cardiomyopathy induced by methamphetamine. Clinical Cardiology. 12: 725-727, 1989.
53. Furst, S.R., Fallon, S.P., Reznik, G.N. and Shah, P.K. Myocardial infarction after inhalation of methamphetamine. New England Journal of Medicine. 323: 1147~1148, 1990.
54. Umar, A., Buermeyer, A.B., Simon, J.A., Thomas, D.C., Clark, A.B., Liskay, R.M. and Kunkel, T.A. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell. 87: 65~73, 1996.
55. Savio, M., Stivala, L.A., Bianchi, L., Vannini, V. and Prosperi, E. Involvement of the proliferating cell nuclear antigen (PCNA) in DNA repair induced by alkylating agents and oxidative damage in human fibroblasts. Carcinogenesis. 19: 591~596, 1998.
56. Larez, A., Briceno, E., Ochoa, Y., Montenegro, M. and Aponte, N. Mutagenicity obtained experimentally by oral administration of dextroamphetamine sulphate to the rat. Bulletin on Narcotics. 31: 67~70, 1979.
57. Shimizu, H., Takemura, N., Ando, H., Morita, M. and Machida, K. Mutagenic activity of N-nitrosomethamphetamine and N-nitrosoephedrine. Cancer Letters. 21: 63~68, 1983.
58. Sen, S., Agarwal, K., Mukherjee, A. and Sharma, A. Potentiation by caffeine of the frequencies of chromosomal aberrations induced by chronic exposure to fenfluramine in mice. Drug & Chemical Toxicology. 17: 113~124, 1994.
59. Agarwal, K., Mukherjee, A., Sharma, A., Sharma, R., Bhardwaj, K.R. and Sen, S. Clastogenic effect of fenfluramine in mice bone marrow cells in vivo. Environmental & Molecular Mutagenesis. 19: 323~326, 1992.
60. Vorhees, C.V., Brunner, R.L. and Butcher, R.E. Psychotropic drugs as behavioral teratogens. Science. 205: 1220~1225, 1979.
61. Fantel, A.G., Barber, C.V., Carda, M.B., Tumbic, R.W. and Mackler, B. Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine. Teratology. 46: 293~300, 1992.
62. Lutiger, B., Graham, K., Einarson, T.R. and Koren, G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology. 44: 405~414, 1991.
63. Budunova, I.V. and Slaga T.J. Alteration of gap junctional intercellular communication during carcinogenesis. Cancer J. 7:228~237,1994.
64. Price, P.J., Gregory, E.A., Skeen, P.C. and Ritalin, Benzedrine and Dexedrine do not transform F 1706 rat cells. Cancer Letters. 5: 345~349, 1978.
65. Martin, J.C., Martin, D.D., Radow, B. and Day, H.E. Life span and pathology in offspring following nicotine and methamphetamine exposure. Experimental Aging Research. 5: 509~522, 1979.
66. Freire-Garabal, M., Nunez, M.J., Balboa, J.L., Suarez, J.A., Gallego, A. and Belmonte, A. Effects of amphetamine on the development of MTV-induced mammary tumors in female mice. Life Sciences. 51: PL37~40, 1992.
67. Freire-Garabal, M., Nunez-Iglesias, M.J. Rey-Mendez, M., Pereiro-Raposo, M.D., Riveiro, P., Fernandez-Rial, J.C., Losada, C., Gandoy, M. and Mayan, J.M. Effects of amphetamine on the development of Moloney sarcoma virus-induced tumors in mice. Oncology Reports. 5: 381~383, 1998.
68. Dubach, U.C., Rosner, B. and Pfister, E. Epidemiologic study of abuse of analgesics containing phenacetin. Renal morbidity and mortality (1968-1979). New England Journal of Medicine. 308: 357~362, 1983.
69. Cadet, J.L., Ali, S.F., Rothman, R.B. and Epstein, C.J. Neurotoxicity, drugs and abuse, and the CuZn-superoxide dismutase transgenic mice. Molecular Neurobiology. 11: 155~163, 1995.
70. Cadet, J.L., Ladenheim, B., Hirata, H., Rothman, R.B., Ali, S., Carlson, E., Epstein, C. and Moran, T.H. Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): evidence from using CuZn-superoxide dismutase transgenic mice. Synapse. 21: 169~176, 1995.
71. Cadet, J.L., Ladenheim, B., Baum, I., Carlson, E. and Epstein, C. CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA). Brain Research. 655: 259~262, 1994.
72. Cohen, G. and Heikkila, R.E. The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. Journal of Biological Chemistry. 249: 2447~2452, 1974.
73. Jamieson, D., Chance, B., Cadenas, E. and Boveris, A. The relation of free radical production to hyperoxia. Annual Review of Physiology. 48: 703~719, 1986.
74. Fridovich, I. The biology of oxygen radicals. Science. 201: 875~880, 1978.
75. Turrens, J.F., Freeman, B.A. and Crapo, J.D. Hyperoxia increases H2O2 release by lung mitochondria and microsomes. Archives of Biochemistry & Biophysics. 217: 411~421, 1982.
76. Turrens, J.F., Freeman, B.A., Levitt, J.G. and Crapo, J.D. The effect of hyperoxia on superoxide production by lung submitochondrial particles. Archives of Biochemistry & Biophysics. 217: 401~410, 1982.
77. Freeman, B.A. and Crapo, J.D. Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. Journal of Biological Chemistry. 256: 10986~10992, 1981.
78. Ames, B.N., Durston, W.E., Yamasaki, E. and Lee, F.D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proceedings of the National Academy of Sciences of the United States of America. 70: 2281~2285, 1973.
79. Ames, B.N. A combined bacterial and liver test system for detection and classification of carcinogens as mutagens. Genetics. 78: 91~95, 1974.
80. Li, A.P., Gupta, R.S., Heflich, R.H. and Wassom, J.S. A review and analysis of the Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase assay to determine the mutagenicity of chemical agents. A report of phase III of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Research. 196: 17~36, 1988.
81. Oberly, T.J., Rexroat, M.A., Bewsey, B.J., Richardson, K.K. and Michaelis, K.C. An evaluation of the CHO/HGPRT mutation assay involving suspension cultures and soft agar cloning: results for 33 chemicals. Environmental & Molecular Mutagenesis. 16: 260~271, 1990.
82. Lasne, C., Gu, Z.W., Venegas, W. and Chouroulinkov, I. The in vitro micronucleus assay for detection of cytogenetic effects induced by mutagen-carcinogens: comparison with the in vitro sister-chromatid exchange assay. Mutation Research. 130: 273~282, 1984.
83. Keshava, C., Ong, T. and Nath, J. Comparative studies on radiation-induced micronuclei and chromosomal aberrations in V79 cells. Mutation Research. 328: 63-71, 1995.
84. Rodilla, V. Origin and evolution of binucleated cells and binucleated cells with micronuclei in cisplatin-treated CHO cultures. Mutation Research. 300: 281-291, 1993.
85. Rodilla, V., Pellicer, J.A., Serrano, A. and Pertusa, J. Possible relationship between micronucleated and binucleated cells induced by cisplatin in cultured CHO cells. Mutation Research. 291: 35-41, 1993.
86. Griffiths, A.J.F., Miller, J.H., Suzuki, D.T., Lewontin, R.C. and Gelbart W.M. An Introduction to Genetic Analysis. 6th Ed.: W.H. Freeman and Company, New York, U.S.A., 211~248, 1996.
87. Galloway, S.M., Bloom, A.D., Resnick, M., Margolin, B.H., Nakamura, F., Archer, P. and Zeiger, E. Development of a standard protocol for in vitro cytogenetic testing with Chinese hamster ovary cells: comparison of results for 22 compounds in two laboratories. Environmental Mutagenesis. 7: 1~51, 1985.
88. Burow, S. and Valet, G. Flow-cytometric characterization of stimulation, free radical formation, peroxidase activity and phagocytosis of human granulocytes with 2,7-dichlorofluorescein (DCF). European Journal of Cell Biology. 43: 128~133, 1987.
89. Radi, R., Beckman, J.S., Bush, K.M. and Freeman, B.A. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Archives of Biochemistry & Biophysics. 288: 481~487, 1991.
90. Beckman, J.S. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. Journal of Developmental Physiology. 15: 53~59, 1991.
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