Advertisement

Metabolic Brain Disease

, Volume 7, Issue 3, pp 139–146 | Cite as

Differential effects of metal ions on type a and type B monoamine oxidase activities in rat brain and liver mitochondria

  • Thomas K. C. Leung
  • Louis Lim
  • James C. K. Lai
Original Contributions

Abstract

To investigate the hypothesis that neurotoxic metals can exert their toxicity through the direct inhibition of monoamine oxidases (MAOs), the effects of several neurotoxic metal ions on type A (MAO-A) and type B (MAO-B) monoamine oxidase activities in rat forebrain nonsynaptic mitochondria and rat liver mitochondria were studied. At pathophysiological levels (10–100 μM), Cu2+ and Cd2+ are good inhibitors of brain mitochondrial MAO-A and, to a lesser extent, liver mitochondrial MAO-A. The inhibition of MAO-B activities in brain and liver mitochondria by Cu2+ and Cd2+ is only detected at the higher end of the concentration range (i.e., 50–100 μM). At the pathophysiological level of 0.5 mM, Al3+ only inhibits brain mitochondrial MAO-A but at the higher level of 2.5 mM, it inhibits both forms of MAO in brain as well as liver mitochondria. Even at toxic levels (e.g., 5 mM), neither Mn2+ nor Li+ inhibits the activities of MAO-A and MAO-B in brain and liver mitochondria. Our results are consistent with the hypothesis that some neurotoxic metals can exert their toxicity through the direct inhibition of the isoforms of MAO. Our data also suggest that the selective inhibition of brain MAO-A by Cu2+ and Cd2+ may assume pathophysiological importance in the neurotoxicity of copper and cadmium.

Key words

metal toxicity monoamine oxidases metal inhibition of monoamine oxidases 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Atterwill, C.K., and Tordoff, A.F.C. (1982). Effects of repeated lithium administration on the subcellular distribution of 5-hydroxytryptamine in rat brain.Brit. J. Pharmacol. 76:413–421.Google Scholar
  2. Bach, A.W., Lan, N.C., Johnson, D.L., Abell, C.W., Bembenek, M.E., Kwan, S.-W., Seeburg, P.H., and Shih, J.C. (1988). cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties.Proc. Natl. Acad. Sci. USA 85:4934–4938.Google Scholar
  3. Grimsby, J., Lan, N.C., Neve, R., Chen, K., and Shih, J.C. (1990). Tissue distribution of human monoamine oxidase A and B mRNA.J. Neurochem. 55:1166–1169.Google Scholar
  4. Holzbauer, M., and Youdim, M.B.H. (1977). Physiological control of monoamine oxidases. In Usdin, E., Weiner, N., and Youdim, M.B.H. (eds.),Structure and Function of Monoamine Enzymes, Marcel Dekker, New York, pp. 601–627.Google Scholar
  5. Hsu, Y.-P.P., Weyler, W., Chen, S., Sims, K.B., Rinehart, W.B., Utterback, M.C., Powell, J.F., and Breakefield, X.O. (1988). Structural features of human monoamine oxidase A elucidated from cDNA and peptide sequence.J. Neurochem. 51:1321–1324.Google Scholar
  6. Johnston, J.P. (1968). Some observations upon a new inhibitor of monoamine oxidase in brain tissue.Biochem. Pharmacol. 17: 1285–1297.Google Scholar
  7. Knoll, J., and Magyar, K. (1972). Some puzzling pharmacological effects of monoamine oxidase inhibitors.Adv. Biochem. Psychopharmacol. 5:393–408.Google Scholar
  8. Kochersperger, L.M., Waguespack, A., Patterson, J.C., Hsieh, C.C., Weyler, W., Salach, J.I., and Denney, R.M. (1985). Immunological uniqueness of human monoamine oxidases A and B: new evidence from studies with monoclonal antibodies to human monoamine oxidase A.J. Neurosci. 5:2874–2881.Google Scholar
  9. Lai, J.C.K., and Barrow, H.N. (1984). Comparison of the inhibitory effects of mercuric chloride on cytosolic and mitochondrial hexokinase activities in rat brain, kidney and spleen.Comp. Biochem. Physiol. 78C:81–87.Google Scholar
  10. Lai, J.C.K., and Blass, J.P. (1984a). Inhibition of brain glycolysis by aluminum.J. Neurochem. 42:438–446.Google Scholar
  11. Lai, J.C.K., and Blass, J.P. (1984b). Neurotoxic effects of copper: inhibition of glycolysis and glycolytic enzymes.Neurochem. Res. 9:1699–1710.Google Scholar
  12. Lai, J.C.K., Chan, A.W.K., Leung, T.K.C., Minski, M.J., and Lim, L. (1992). Neurochemical changes in rats chronically treated with a high concentration of manganese chloride.Neurochem. Res. (in press).Google Scholar
  13. Lai, J.C.K., and Clark, J.B. (1979). Preparation of synaptic and non-synaptic mitochondria from mammalian brain. In Fleischer, S., and Packer, L. (eds.),Methods in Enzymology,Vol. 55, Part F, Academic Press, New York, pp. 51–60.Google Scholar
  14. Lai, J.C.K., and Clark, J.B. (1989). Isolation and characterization of synaptic and non-synaptic mitochondria from mammalian brain. In Boulton, A.A., Baker, G.B., and Butterworth, R.F. (eds.),NeuroMethods,Vol. 11, Humana Press, Clifton, NJ, pp. 43–98.Google Scholar
  15. Lai, J.C.K., Guest, J.F., Leung, T.K.C., Lim, L., and Davison, A.N. (1980). The effects of cadmium, manganese and aluminum on sodium-potassium-activated and magnesium-activated adenosine triphosphatase activity and choline uptake in rat brain synaptosomes.Biochem. Pharmacol. 29:141–146.Google Scholar
  16. Lai, J.C.K., Leung, T.K.C., and Lim, L. (1982). Monoamine oxidase activities in liver, heart, spleen and kidney of the rat: organ-specific changes in aging and after chronic manganese chloride administration.Exp. Gerontol. 17:219–225.Google Scholar
  17. Lai, J.C.K., Leung, T.K.C., and Lim, L. (1985). Effects of metal ions on neurotransmitter function and metabolism. In Gabay, S., Harris, J., and Ho, B.T. (eds.),Metal Ions in Neurology and Psychiatry (Neurology and Neurobiology),Vol. 15, Alan Liss, New York, pp. 177–197.Google Scholar
  18. Lai, J.C.K., Walsh, J.M., Dennis, S.C., and Clark, J.B. (1977). Synaptic and non-synaptic mitochondria from rat brain: isolation and characterization.J. Neurochem. 28:625–631.Google Scholar
  19. Lai, J.C.K., Wong, P.C.L., and Lim, L. (1983). Structure and function of synaptosomal and mitochondrial membranes: elucidation using neurotoxic metals and neuromodulatory agents. In Sun, G.Y., Bazan, N., Wu, J.-Y., Porcellati, G., and Sun, A.Y. (eds.),Neural Membranes, Humana Press, Clifton, NJ, pp. 355–374.Google Scholar
  20. Leung, T.K.C., Lai, J.C.K., Marr, W., and Lim, L. (1980). The activities of the A and B forms of monoamine oxidase in liver, hypothalamus and cerebral cortex of the female rat: effects of administration of ethinyl oestradiol and the progestogens norethisterone acetate and D-norgestrel.Biochem. Soc. Trans. 8:615–616.Google Scholar
  21. Leung, T.K.C., Lai, J.C.K., and Lim, L. (1981). The regional distribution of monoamine oxidase activities towards different substrates: effects in rat brain of chronic administration of manganese chloride and of ageing.J. Neurochem. 36:2037–2043.Google Scholar
  22. Leung, T.K.C., Lai, J.C.K., and Lim, L. (1982). The effects of chronic manganese feeding on the activity of monoamine oxidase in various organs of the developing rats.Cornp. Biochem. Physiol. 71C:223–228.Google Scholar
  23. Owen, F., Bourne, R.C., Lai, J.C.K., and Williams, R. (1977). The heterogeneity of monoamine oxidase in distinct populations of rat brain mitochondria.Biochem. Pharmacol. 26:289–292.Google Scholar
  24. Powell, J.F., Hsu Y.-P.P., Weyler, W., Chen, S., Salach, J.I., Andrikopoulos, K., Mallet, J., and Brcakefield, X.O. (1989). The primary structure of bovine monoamine oxidase type A: comparison with peptide sequences of bovine monoamine oxidase type B and other flavoenzymes.Biochem. J. 259, 407–413.Google Scholar
  25. Shih, J.C., Grimsby, J., and Chen, K. (1990). The expression of human MAO-A and B genes.J. Neural Transm. Suppl. 32, 41–47.Google Scholar
  26. Tipton, K.F., Houslay, M.D., and Mantle, T.J. (1976). The nature and locations of the multiple forms of monoamine oxidase. InMonoamine Oxidase and Its Inhibition (Ciba Foundation Symposium39, new series), Elsevier, Amsterdam, pp. 5–31.Google Scholar
  27. Underwood, E.J. (1977).Trace Elements in Human and Animal Nutrition, 4th Ed., Academic Press, New York, pp. 440–442.Google Scholar

Copyright information

© Plenum Publishing Corporation 1992

Authors and Affiliations

  • Thomas K. C. Leung
    • 1
  • Louis Lim
    • 1
  • James C. K. Lai
    • 2
  1. 1.Department of Neurochemistry, Institute of NeurologyUniversity of London, Queen SquareLondon WC1N 3BGUK
  2. 2.Department of Pharmaceutical Sciences and Center for Toxicology ResearchCollege of Pharmacy, Idaho State UniversityPocatelloUSA

Personalised recommendations