ß-Carboline Analogues of MPP+ as Environmental Neurotoxins

  • Michael A. Collins
  • Edward J. Neafsey


Carbolines (pyrido-indoles) are prevalent tryptophan-derived heterocyclics in the diet and environment that have been linked since the late 1970’s to carcinogenesis. Evidence from our and other laboratories suggests the possibility that the most common pyrido-indole isomers, the ß-carbolines, also might be “protoxicants” leading to neuronal damage and resultant idiopathic parkinsonism in susceptible individuals. There is a close structural similarity between the N-methylated cationic products of simple ß-carbolines (e.g., norharman or harman) and the parkinsonian neurotoxin, MPTP, or specifically, its active cationic metabolite, MPP+. The N-methylated ß-carbolinium species are formed in mammalian brain via one or possibly two enzymatic S-adenosylmethionine-dependent N-methylations. These chemical alterations metabolically bioactivate the molecules, greatly increasing both the mitochondrial inhibitory activity and the in vitro and in vivo dopaminergic toxicity of the ß-carboline nucleus. Furthermore, the second (indole nitrogen) methylating activity as well as the product (2,9-di-N-methylated) carbolinium cations appear to be elevated in parkinsonian brain. Matsubara’s studies (this volume) demonstrate nigrostriatal neurodegeneration and neurobehavioral impairment in mice given precursors of the ß-carbolinium cations. In view of these findings, epidemiological studies on the possible relationship between environmental carboline alkaloid exposure and idiopathic parkinsonism could be revealing.


PC12 Cell Pyridinium Cation Mesencephalic Culture Indole Nitrogen Dopaminergic Toxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adachi, H., Mizoi, Y., Naito, T., Ogawa, Y., Uetani, Y. and Ninomiya, L, 1991, Identification of tetrahydro-ß-carboline-3-carboxylic acid in foodstuffs, human urine and human milk,J. Nutr. 121: 646.PubMedGoogle Scholar
  2. Adell, A. and Myers, R.D., 1994, Increased alcohol intake in low alcohol drinking rats after chronic infusion of the ß-carboline harman into the hippocampus,Pharmacol. Biochem. Behav.49: 949.PubMedCrossRefGoogle Scholar
  3. Airaksinen, M.M. and Kari, I., 1981, Beta-carbolines, psychoactive compounds in the mammalian body,Med. Biol. 59: 21.PubMedGoogle Scholar
  4. Albores, R., Jr., Neafsey, E.J., Drucker, G., Fields, J.Z. and Collins, M.A., 1990, Mitochondrial respiratory inhibition by N-methyl-ß-carboline derivatives structurally resembling MPP+,Proc. Natl. Acad. Sci. USA 87: 9368.PubMedCrossRefGoogle Scholar
  5. Allen J.R. and Holmstedt, B., 1980, The simple ß-carboline alkaloids,Phytochem.19: 1573.CrossRefGoogle Scholar
  6. Ansher, S. and Jacoby, W.B., 1986, Amine N-methyltransferases from rabbit liver,J. Biol. Chem. 261: 3996.PubMedGoogle Scholar
  7. Ansher, S., Cadet, J., Jacoby, W.B. and Baker, J., 1986, Role of N-methyltransferases in the neurotoxicity associated with metabolites of MPTP and other 4-substituted pyridines in the environment,Biochem. Pharmacol.35: 3359.PubMedCrossRefGoogle Scholar
  8. Arora, P.K., Riachi, N.J., Fiedler, G.C., Singh, M.P., Abdallah, F., Harik, S.I. and Sayre, L.M., 1990, Structure-neurotoxicity trends of analogues of MPP+, the cytotoxic metabolite of dopaminergic neurotoxin MPTP,Life Sci. 46: 379.PubMedCrossRefGoogle Scholar
  9. Barker, S., Harrison, R.E.W., Monti, J., Brown, G.B. and Christian, S.T., 1981, Identification and quantification of 1,2,3,4-tetrahydro-ß-carboline, 2-methyl-1,2,3,4-tetrahydro-ß-carboline, and 6-methoxy-l,2,3,4-tetrahydro- carboline as in vivo constituents of rat brain and adrenal gland,Biochem. Pharmacol.30: 9.PubMedCrossRefGoogle Scholar
  10. Beck, O., Faull, K. and Repke, D., 1986, Rapid hydroxylation of methtryptoline (1-methyltetrahydro-ß-carboline) in rat: identification of metabolites by chiral gas chromatography-mass spectrometry,Arch. Pharmacol.333: 307.CrossRefGoogle Scholar
  11. Bosin, T.R., Krogh, S. and Mais, D., 1986, Identification and quantitation of 1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid and l-methyl-l,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid in beer and wine,J. Agric. Food Chem. 34: 843.CrossRefGoogle Scholar
  12. Breyer-Pfaff, U., Wiatr, G., Stevens, L, Gaertner, H.J., Mundle, G. and Mann, K., 1996, Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking,Life Sci. 58: 1425.PubMedCrossRefGoogle Scholar
  13. Bringmann, G., Feineis, D., Friedrich, H. and Hille, A., 1991, Endogenous alkaloids in mansynthesis, analytics,Planta Med. 57[Suppl.]: 73.CrossRefGoogle Scholar
  14. Buckholtz, N.S. and Boggan, W.O., 1977, Monoamine oxidase inhibition in brain and liver produced by ß-carbolines: structure-activity relationships and substrate specificity,Biochem. Pharmacol.26: 1991.PubMedCrossRefGoogle Scholar
  15. Castagnoli, N. Jr., Rimoldi, J.M., Bloomquist, J., and Castagnoli, K.P., 1997, Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes,Chem. Res. Toxicol.10: 294.Google Scholar
  16. Cheekoway, H. and Nelson, L.M., 1999, Epidemiologic approaches to the study of Parkinson’s disease etiology, Epidemiol. 10: 327.CrossRefGoogle Scholar
  17. Cleeter, M., Cooper, J.M. and Schapira, A.H.V., 1992, Irreversible inhibition of mitochondrial complex I by MPP+: evidence for the free radical involvement,Biochem. Biophys. Res. Commun. 105: 1368.Google Scholar
  18. Cobuzzi, R. Jr., Neafsey, E.J. and Collins, M.A., 1994, Differential cytotoxicities of N-methyl-ß-carbolinium analogs of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson’s disease,J. Neurochem.62: 1503.PubMedCrossRefGoogle Scholar
  19. Collins, M.A. and Neafsey, E.J., 1985, ß-Carboline analogs of N-methyl-4-phenyl-l,2,5,6-tetrahydro-pyridine (MTP): endogenous factors underlying idiopathic parkinsonism?Neurosci. Lett. 55: 179.PubMedCrossRefGoogle Scholar
  20. Collins, M.A. and Neafeey, E.J., 1998, ß-Carboline derivatives as neurotoxins, in (A. Moser, Ed.)Pharmacology of Endogenous Neurotoxins: A Handbook, Birkhauser Boston, p. 129.Google Scholar
  21. Collins, M. A., Neafsey, E.J., Cheng, B.Y., Hurley-Gius, K., Ung-Chhun, N.A., Pronger, D.A., Christiansen, M.A. and Hurley-Gius, D., 1986, Endogenous analogs of MPTP: Indoleaminederived tetrahydro-ß-carbolines as potential causative factors in Parkinson’s disease,Adv. Neurol.45: 179.Google Scholar
  22. Collins, M.A., Neafeey, E.J., Matsubara, K., Cobuzzi, R., and Rollema, EL, 1992, Indole-N-methylated ß-carbolinium ions as potential brain-bioactivated neurotoxins,Brain Res. 570:154.PubMedCrossRefGoogle Scholar
  23. Collins, M.A., Slobodnik, L. and Neafsey, E.J., 1995, Inhibitors of NO synthase and poly (ADP-ribose) synthase (PARS) do not block toxic actions of ß-carbolinium cations or MPP+ in mesencephalic cultures,Abst. Soc. Neurosci.21: 1259.Google Scholar
  24. Collins, M.A., Neafsey, E.J. and Matsubara, K., 1996, ß-Carbolines: metabolism and neurotoxicity,Biogen. Amines 12: 171.Google Scholar
  25. Cox, E.D. and Cook, J.M., 1995, The Pictet-Spengler condensation - A new direction for an old reaction,Chem. Rev. 95: 1797.CrossRefGoogle Scholar
  26. Crooks, P.A., Godin, C.S., Nwosu, C, Ansher, S. and Jacoby, W.B., 1986, Reevaluation of the products of tryptamine catalyzed by rabbit liver N-methyltransferases,Biochem. Pharmacol.35: 1600.PubMedCrossRefGoogle Scholar
  27. Crooks P.A., Godin C.S., Damani L.A., Ansher S.S. and Jakoby W.B., 1988, Formation of quaternary amines by N-methylation of azaheterocycles with homogeneous amine N-methyl-transferases,Biochem. Pharmacol.37: 1673.PubMedCrossRefGoogle Scholar
  28. Dillon, J., Spector, A. and Nakanishi, K., 1976, Identification of ß-carbolines from fluorescent human lens proteins,Nature 259: 422.PubMedCrossRefGoogle Scholar
  29. Drucker, G., Raikoff, K., Neafeey, E.J. and Collins, M.A., 1989, Dopamine uptake inhibitory capacities of ß-carboline and 3,4-dihydro-)ß-carboline analogs of MPTP oxidation products,Brain Res. 509: 125.CrossRefGoogle Scholar
  30. Eatough, V.M., Kempster, P.A., Stern, G.M. and Lees, A.J., 1990, Premorbid personality and idiopathic Parkinson’s disease,Adv. Neurol.53: 335.PubMedGoogle Scholar
  31. Fekkes, D., Schouten, M., Pepplinkhuizen, L., Bruinvels, J., Lauwers, W. and Brinkman, U., 1992, Norharman, a normal body constituent,Lancet 339: 506.PubMedCrossRefGoogle Scholar
  32. Fekkes, D. and Bode W.T., 1993, Occurrence and partition of the beta-carboline norharman in rat organs,Life Sci. 52: 2045.PubMedCrossRefGoogle Scholar
  33. Felton, J.S. and Knize, M.G., 1990, Heterocyclic-amine mutagens/carcinogens in foods, in: Hdbk.Exp. Pharmacol.94: 471.Google Scholar
  34. Fields, J.Z., Albores, R., Neafeey, E.J. and Collins, M.A., 1992, Inhibition of mitochondrial succinate oxidation-similarities and differences between N-methylated ß-carbolines and MPP+,Arch. Biochem. Biophys.294: 539.PubMedCrossRefGoogle Scholar
  35. Fukushima, S., Matsubara, K., Akane, A. and Shiono, H., 1991, l-Methyl-tetrahydro-ß-carbo-line-3-carboxylic acid is present in rat brain and is not increased after acute ethanol injection with cyanamide treatment,Alcohol 9: 31.CrossRefGoogle Scholar
  36. Gearhart, D.A., Collins, M.A. and Neafeey, E.J., 1995, Preliminary characterization of ß-carboline 2-N-methyltransferase from mammalian brain,Abst. Soc. Neurosci. 21: 1252.Google Scholar
  37. Gearhart, D.A., Neafeey, E.J. and Collins, M.A., 1996, ß-Carboline-N-methyltransferase activity in human brain tissue from control and Parkinson’s disease subjects,Abst. Soc. Neurosci. 22: 217.Google Scholar
  38. Gearhart, D.A., Collins, M.A. and Neafsey, E.J., 1997, Characterization of brain ß-carboline 2-N-methyl-transferase, an enzyme that may play a role in idiopathic Parkinson’s disease,Neurochem. Res. 22: 113.PubMedCrossRefGoogle Scholar
  39. Gearhart, D.A., 1997,N-Methylation ofß-carbolines as a potential bioactivation route in Parkinson’s disease, Ph.D. Thesis, Loyola University Chicago, Chicago IL.Google Scholar
  40. Gearhart, D.A., Collins, M.A., Lee, J. and Neafeey, E.J., 2000, Increased brain ß-carboline-9N-methyltransferase activity in the frontal cortex in Parkinson’s disease,Neurobiol. Dis. 7: 201.PubMedCrossRefGoogle Scholar
  41. Godin, C.S., Crooks, P.A. and Damani, L., 1986, N-Methylation of phenylpyridines and bipyridyls as a potential toxication route. Tissue distribution of azaheterocycle N-methyltransferase activity,Toxicol. Lett 34: 217.PubMedCrossRefGoogle Scholar
  42. Godin, C.S. and Crooks, P.A., 1989,N-Methylation as a toxication route for xenobiotics. II. in vivo formation of the N,N’-dimethyl-4,4’-bipyridyl ion (paraquat) from 4,4’-bipyridyl in the guinea pig,Drug Metab. Dispos. 17: 180.PubMedGoogle Scholar
  43. Gorell, J.M., Rybicki, B.A., Johnson, C.C., and Peterson, E.L., 1999, Smoking and PD: A dose-response relationship,Neurology 52: 115.PubMedCrossRefGoogle Scholar
  44. Harrison, R.E.W., 1982, Stress elevation of brain and adrenal levels of non-polar tryptophan metabolites, Ph.D. Thesis, University of Alabama, Birmingham AL.Google Scholar
  45. Hasegawa, S., Matsubara, K., Takahashi, A., Naoi, M. and Nagatsu, T., 1995, Inhibition of type A monoamine oxidase by N-methyl ß-carbolinium ions,Biogen. Amines 11: 295.Google Scholar
  46. Heikkila, R.E., Manzino, L., Cabbat, F.S., and Duvoisin, R.C., 1984, Protection against the dopaminergic neurotoxicity of MPTP by monoamine oxidase inhibitors,Nature 311: 467.PubMedCrossRefGoogle Scholar
  47. Heikkila, R.E, Sieber, B.A., Manzino, L. and Sonsalla, P., 1989, Some features of the nigrostriatal dopaminergic neurotoxin MPTP in the mouse,Mol. Cell. Neuropathol.10: 171.CrossRefGoogle Scholar
  48. Herderich M. and Gutsche B., 1997, Tryptophan-derived bioactive compounds in food,Food Rev. Int. 13: 103.CrossRefGoogle Scholar
  49. Herraiz, T., Huang, Z. and Ough, S., 1993, l,2,3,4-Tetrahydro-ß-carboline-3-carboxylic acid and l-methyl-l,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid in wines,J. Agric. Food Chem. 41: 455.CrossRefGoogle Scholar
  50. Higashimoto, M., Yamamoto, T., Kinouchi, T., Matsumoto, H. and Ohnishi, Y., 1996, Mutagenicity of l-methyl-l,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid treated with nitrite in the presence of alcohols,Mutat. Res. 367: 43.PubMedCrossRefGoogle Scholar
  51. Ho, B.T., Gardner, P.M. and Walker, K.E., 1973, Inhibition of MAO by ß-carbolinium halides,J. Pharm. Sci. 62: 36.PubMedCrossRefGoogle Scholar
  52. Hoppel, C.L., Greenblatt, D., Kwok, H.-C., Arora, P.K., Singh, M.P. and Sayre, L.M., 1987, Inhibition of mitochondrial respiration by analogs of 4-phenylpyridine and MPP+, the neurotoxic metabolite of MPTP,Biochem. Biophys. Res. Commun. 148: 684.PubMedCrossRefGoogle Scholar
  53. Hung, H.C., Tao, P.L. and Lee, E.H., 1995, MPP+ uptake does not explain the differential toxicity of MPP+ in the nigrostriatal and mesolimbic pathways,Neurosci. Lett. 196: 93.PubMedCrossRefGoogle Scholar
  54. Javitch, J.A., D’Amato, R.J., Strittmatter, S.M. and Snyder, S.H., 1985, Parkinsonism-inducing neurotoxin, MPTP: Uptake of metabolite MPP+ by dopamine neurons explains selective toxicity,Proc. Natl. Acad. Sci. USA 82: 2173.PubMedCrossRefGoogle Scholar
  55. Kim, H., Sablin S.O. and Ramsay, R.R., 1997, Inhibition of monoamine oxidase A by ß-carboline derivatives,Arch. Biochem. Biophys.337: 137.PubMedCrossRefGoogle Scholar
  56. Krueger, M.J., Tan, A.K., Ackrell, B.A. and Singer, T.P., 1993, Is Complex II involved in the inhibition of mitochondrial respiration by MPP+ and N-methyl-ß-carbolines?Biochem. J. 291: 673.PubMedGoogle Scholar
  57. Kuhn, W., Muller, Th., Grobe, H., Dierks, T. and Rommelspacher, H., 1995, Plasma levels of the ß-carbolines, harman and norharman, in Parkinson’s disease,Acta Neurol. Scand.92: 451.PubMedCrossRefGoogle Scholar
  58. Langston, J.W., Irwin, I., Langston, E.B., and Forno, L.S., 1984, Pargyline prevents MPTP-induced parkinsonism in primates,Science 225: 1480.PubMedCrossRefGoogle Scholar
  59. Malgrange, B., Rigo, J.-M., Coucke, P., Belachew, S., Rogister, B., and Moonen, G., 1996,ß-Carbolines induce apoptotic death of cerebellar neurones in culture,NeuroReport 7: 3041.PubMedCrossRefGoogle Scholar
  60. Manabe, S., Yuan, J., Takahashi, T. and Urban, R.C. Jr., 1996, Age-related accumulation of 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid in human lens,Exp. Eye Res. 63: 179.PubMedCrossRefGoogle Scholar
  61. Markey, S.P., Johannessen, J.N., Chiueh, C.C., Burns, R.S., and Herkenham, M.A., 1984, Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism,Nature 311: 464.PubMedCrossRefGoogle Scholar
  62. Matsubara, K., 1996, Occurrence of neurotoxic ß-carbolinium cations in mammalian central nervous system,Biogen. Amines 12: 161.Google Scholar
  63. Matsubara, K., Collins, M.A. and Neafsey, E.J., 1992a, Mono-N-methylation of 1,2,3,4-tetrahydro-ß-carbolines in brain cytosol: absence of indole methylation,J. Neurochem.59: 505.PubMedCrossRefGoogle Scholar
  64. Matsubara, Neafsey, E.J. and Collins, M.A., 1992b, Novel S-adenosylmethionine-dependent indole-N-methylation ofß-carbolines in brain particulate fractions,J. Neurochem.59: 511.PubMedCrossRefGoogle Scholar
  65. Matsubara, K., Collins, M.A., Akane, A., Ikebuchi, J., Neafsey, E.J., Kagawa, M. and Shiono, H.,1993, Potential bioactivated neurotoxicants,N-methylatedß-carbolinium ions, are present in human brain,Brain Res. 610: 90.PubMedCrossRefGoogle Scholar
  66. Matsubara, K., Kobayashi, S., Kobayashi, Y., Yamashita, K., Koide, H., Hatta, M., Iwamoto, K., Tanaka, O. and Kimura, K., 1995,ß-Carbolinium cations, endogenous MPP+ analogs, in the lumbar cerebrospinal fluid of patients with Parkinson’s disease,Neurology 45: 2240.PubMedCrossRefGoogle Scholar
  67. Melchior, CM. and Collins, M.A., 1982, The routes and significance of endogenous synthesis of alkaloids in animals,CRC Crit. Rev. Toxicol. 10: 313.CrossRefGoogle Scholar
  68. Naoi, M., Matsuura, S., Takahashi, T. and Nagatsu, T.,1989, A methyltransferase in human brain catalyzesN-methylation of 1,2,3,4-tetrahydroisoquinoline intoN-methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin,N-methylisoquinoliniumion,Biochem. Biophys. Res. Commun.161: 1213.PubMedCrossRefGoogle Scholar
  69. Neafsey, E.J., Drucker, G., Raikoff, K. and Collins, M.A., 1989, Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, aß-carbolinium analog ofN-methyl-4-phenyl-pyridinium ion,Neurosci Lett.105: 344.PubMedCrossRefGoogle Scholar
  70. Neafsey, E.J., Albores, R., Gearhart, D., Kindel, G., Raikoff, K., Tamayo, F. and Collins, M.A. (1995) Methyl-ß-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantianigra injections in rats,Brain Res. 675: 279.PubMedCrossRefGoogle Scholar
  71. Neef, G., Eder, U., Petzoldt, K., Seeger, A. and Wieglepp, H., 1982, Microbial hydroxylations ofß-carboline derivatives,J. Chem. Soc. Chem. Commun. 366.Google Scholar
  72. Nicklas, W., Vyas, I. and Heikkila, R., 1985, Inhibition of NADH-linked oxidation in brain mitochondria by l-methyl-4-phenylpyridine, a metabolite of the neurotoxin, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine,Life Sci. 36: 2503.PubMedCrossRefGoogle Scholar
  73. Ohkubo, S., Toshihiko, H. and Oka, K., 1985, Methyltetrahydro-ß-carbolines and PD,Lancet i: 1272.CrossRefGoogle Scholar
  74. Papavergou, E.J. and Clifford, M.N., 1992, Tetrahydro-ß-carboline-3-carboxylic acids in smoked foods,Food Add. Contamin.9: 83.CrossRefGoogle Scholar
  75. Pari, K., Sundari, C.S., Chandani, S., and Balasubramanian, D., 2000,ß-Carbolines that accumulate in human tissues may serve a protective role against oxidative stress,J. Biol. Chem. 275: 2455.PubMedCrossRefGoogle Scholar
  76. Parker W.D. and Swerdlow R.H., 1998, Mitochondrial dysfunction in idiopathic PD,Amer. J. Hum. Gen. 62: 758.CrossRefGoogle Scholar
  77. Pena, C., Medina, J.H., Novas, M.L., Paladini A.C., and De Robertis, E. (1986) Isolation and identification in bovine cerebral cortex ofn-butyl-ß-carboline-3-carboxylate, a potent benzodiazepine binding inhibitor,Proc. Natl. Acad. Sci. USA 83: 4952.PubMedCrossRefGoogle Scholar
  78. Perry, T.L., Yong, V.W., Wall, R.A. and Jones, K., 1986, Paraquat and two endogenous analogs of the neurotoxic substance MPTP do not damage dopaminergic nigrostriatal neurons in the mouse,Neurosci. Lett 69: 285.PubMedCrossRefGoogle Scholar
  79. Raha, A., Wagner, C., MacDonald, R. and Bresnick, E., 1994, Rat liver cytosolic 4S polycyclicaromatic hydrocarbon-binding protein is glycine-N-methyltransferase,J. Biol. Chem. 269: 5750.PubMedGoogle Scholar
  80. Ramsden, D.B. and William, A.C., 1985, Production in nature of compounds resembling MPTP, a possible cause of Parkinson’s disease,Lancet i: 215.CrossRefGoogle Scholar
  81. Rollema, H., Booth, R. and Castagnoli, N.J., 1988, in vivo dopaminergic neurotoxicity of the 2-ß-methylcarbolinium ion, a potential endogenous MPP+ analog, Eur. J. Pharmacol. 153: 131.PubMedCrossRefGoogle Scholar
  82. Rommelspacher, H., May, T., and Salewski, B., 1994, Harman (l-methyl-ß-carboline) is a natural inhibitor of monoamine oxidase A in rats,Europ. J. Pharmacol.252: 51.CrossRefGoogle Scholar
  83. Rommelspacher, H. and Schmidt, L., 1995, Tetrahydroisoquinolines andß-carbolines: putative natural substances in plants and mammals,Prog. Drug Res. 415.Google Scholar
  84. Saavedra, J.M., Coyle, J.T. and Axelrod, J., 1973, The distribution and properties of the non-specificN-methyltransferase in brain,J. Neurochem.20: 743.PubMedCrossRefGoogle Scholar
  85. Sayre, L.M., Wang, F., Arora, P.K., Riachi, N.J., Harik, S.I. and Hoppel, C.L., 1991, Dopaminergic neurotoxicity in vivo and inhibition of mitochondrial respiration in vitro by possible endogenous pyridinium-like substances,J. Neurochem.57: 2106.PubMedCrossRefGoogle Scholar
  86. Schouten, M.J. and Bruinvels, J., 1986, Endogenously formed norharman (ß-carboline) in platelet-rich plasma obtained from porphyric rats,Pharmacol. Biochem. Behav. 24: 1219.PubMedCrossRefGoogle Scholar
  87. Sen, N.P., Seaman, S.W., Lau, B., Weber, D. and Lewis, D., 1995, Determination and occurrence of various tetrahydro-ß-carboline-3-carboxylic acids and the correspondingN-nitroso compounds in foods and alcoholic beverages,Food Chem. 54: 327.CrossRefGoogle Scholar
  88. Spies, CD., Rommelspacher, H., Schnapper, C., Muller, C, Marks, C, Berger, G., Conrad, C, Blum, S., Specht, M., Hannemann, L., Striebel, H. and Schaffartzik, W., 1995,ß-Carbolines in chronic alcoholics undergoing elective tumor resection,Alc. Clin. Exp. Res. 19: 969.CrossRefGoogle Scholar
  89. Sugimura, T. and Nagao, M., 1979, Mutagenic factors in cooked foods,CRC Crit. Rev. Toxicol.6: 189.PubMedCrossRefGoogle Scholar
  90. Tanner, C.M. and Langston, W., 1990, Do environmental toxins cause Parkinson’s disease? A critical review,Neurology 40: 17.PubMedGoogle Scholar
  91. Tanner, CM. and Goldman, S.M., 1996, Epidemiology of Parkinson’s disease,Neurol. Clin. 14: 317.PubMedCrossRefGoogle Scholar
  92. Testa, B., Naylor, R., Costall, B., Jenner, P. and Marsden, CD., 1985, Does an endogenous methyl-pyridinium analogue cause Parkinson’s disease?J. Pharm. Pharmacol.37: 679.PubMedCrossRefGoogle Scholar
  93. Tipton, K.F. and Singer, T.P., 1993, Advances in our understanding of the mechanism of the neurotoxicity of MPTP and related compounds,J. Neurochem.61: 1191.PubMedCrossRefGoogle Scholar
  94. Totsuka, Y., Ushiyama, H., Ishihara, J., Sinha, R., Goto, S., Sugimura, T., and Wakabayashi, K., 1999, Quantification of the co-mutagenicß-carbolines, norharman and harman, in cigarette smoke condensates and cooked foods,Cancer Lett. 143: 139.PubMedCrossRefGoogle Scholar
  95. Tsuchiya, H., Todoriki, H. and Hayashi, T., 1995a, Metabolic hydroxylation of 1-methyl-l,2,3,4-tetrahydro-ß-carboline in humans,Pharmacol. Biochem. Behav.52: 677.PubMedCrossRefGoogle Scholar
  96. Tsuchiya, H., Yamada, K., Tajima, K. And Hayashi, T., 1996, Urinary excretion of tetrahydro-ß-carbolines relating to ingestion of alcoholic beverages,Ale. Alcohol.31: 197.CrossRefGoogle Scholar
  97. Tsuchiya H., Hayashi H., Sato M., Shimizu H., and Iinuma M., 1999, Quantitative analysis of all types ofß-carboline alkaloids in medicinal plants and dried edible plants by high performance liquid chromatography with selective fluorometric detection,Phytochem. Anal. 10: 247.CrossRefGoogle Scholar
  98. Turner, B.B., Katz, R.J., Roth, K.A. and Carroll, B.J., 1978, Central elevation of phenylethanol-amine-N-methyltransferase following stress,Brain Res. 153: 419.PubMedCrossRefGoogle Scholar
  99. Ushiyama, H., Oguri, A., Totsuka, Y., Itoh, H., Sugimura, T. and Wakabayashi, K., 1995, Norharman and harman in human urine,Proc. Jpn. Acad. 71B: 57.Google Scholar
  100. Wakabayashi, K., Ochiai, M., Saito, H., Tsuda, M., Suwa, Y., Nagao, M. and Sugimura, T., 1983, Presence of 1-methyl-l,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid, a precursor of mutagenic nitroso compound, in soy sauce,Proc. Natl. Acad. Sci. USA 80: 2912.PubMedCrossRefGoogle Scholar
  101. Wakabayashi, K., Totsuka, Y., Pukutome, K., Oguri, A., Ushiyama, H., and Sugimura, T., 1997, Human exposure to mutagenic/carcinogenic heterocyclic amines and comutagenicß-carbolines,Mutation Res. 376: 253.PubMedCrossRefGoogle Scholar
  102. Williams, A.C., Pall, H.S., Steventon, G.B., Green, S., Buttrum, S., Molloy, H. and Waring, R.H., 1993,N-Methylation of pyridines and Parkinson’s disease,Adv. Neurol.60: 194.PubMedGoogle Scholar
  103. Yuan, J. and Manabe, S., 1995,N-Methyl-ß-carboline-3-carboxamide (FG 7142), an anxiogenic agent in airborne particles and cigarette smoke-polluted indoor air,Environ. Pollution 90: 349.CrossRefGoogle Scholar
  104. Yuan, J. and Manabe, S., 1996, Evaluation of exposure level ofN-methyl-ß-carboline-3-carbox-amide (FG 7142), an anxiogenic agent in humans,Environ. Pollution 94: 267.CrossRefGoogle Scholar
  105. Zheng, W., Wang, S.Z., Barnes, L.F., Guan, Y.B., and Louis, E.D., 2000, Determination of harmane and harmine in human blood using reversed-phased high-performance liquid chromatography and fluorescence detection,Anal. Biochem.279: 125.PubMedCrossRefGoogle Scholar
  106. Ziegler, M.G., Kennedy, B.P. and Houts, F.W., 1998, Extra-adrenal nonneuronal epinephrine and phenylethanolamine-N-methyltransferase,Adv. Pharmacol.42: 843.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Michael A. Collins
    • 1
    • 2
  • Edward J. Neafsey
    • 2
  1. 1.Division of Molecular & Cellular BiochemistryMaywood
  2. 2.Department of Cell Biology, Neurobiology & AnatomyLoyola University Stritch School of MedicineMaywoodUSA

Personalised recommendations