Abstract
Administration of methionine sulfoximine (MSO) to rats and mice significantly decreased cerebral levels ofS-adenosyl-l-homocysteine (AdoHcy). Concurrent administration of methionine prevented this decrease and, when methionine was given alone, significantly elevated AdoHcy levels resulted in both species. Regionally, AdoHcy levels varied from 20 nmol/g in rat cerebellum and spinal cord to about 60 nmol/g in hypothalamus and midbrain. MSO decreased AdoHcy in all regions tested except striatum, midbrain, and spinal cord. AdoMet/AdoHcy ratios (methylation index) varied from 0.48 in hypothalamus to 2.4 in cerebellum, and MSO administration decreased these ratios in all regions except hypothalamus. AdoHcy hydrolase activity was lowest in hypothalamus, highest in brainstem and, generally, varied inversely with regional AdoHcy levels. MSO decreased AdoHcy hydrolase activity in all regions except hypothalamus and spinal cord. Cycloleucine administration resulted in significantly decreased levels of mouse brain AdoHcy, whereas the administration of dihydroxyphenylalanine (DOPA) failed to affect AdoHcy levels. It is concluded that (a) cerebral AdoHcy levels are more tightly regulated than are those of AdoMet after MSO administration, (b) slight fluctuations of AdoHcy levels may be important in regulating AdoHcy hydrolase activity and hence AdoHcy catabolism in vivo, (c) the AdoMet/AdoHcy ratio reflects the absolute AdoMet concentration rather than the transmethylation flux, (d) the decreased AdoMet levels in midbrain, cortex, and striatum after MSO with no corresponding decrease in AdoHcy suggest an enhanced AdoMet utilization, hence an increased transmethylation in the MSO preconvulsant state.
Similar content being viewed by others
References
Schatz, R. A., andSellinger, O. Z. 1975. Effect of methionine and methionine sulfoximine on rat brain S-adenosyl-methionine levels.J. Neurochem. 24:63–66.
Schatz, R. A., andSellinger, O. Z. 1975. The elevation of cerebral histamine-N-and catechol-O-methyl transferase activities byl-methionine-d,l-sulfoximine.J. Neurochem. 25:73–78.
DeRobertis, E., Sellinger, O. Z., Rodriguez de Lores Arnaiz, G., Alberici, M., andZieher, L. M. 1967. Nerve endings in the methionine sulfoximine convulsant rats, a neurochemical and ultrastructural study.J. Neurochem. 14:81–89.
Lombardini, J. B., Coulter, A. W., andTalalay, P. 1970. Analogues of methionine as substrates and inhibitors of the methionine adenosyltransferase action.Molec. Pharmacol. 6:481–499.
Schatz, R. A., Diez Altares, M. C., andSellinger, O. Z. 1973. Effect of methionine (MET) and methionine sulfoximine (MSO) on rat brain S-adenosylmethionine (SAM).Trans. Am. Neurochem. Soc. 4:74.
Zappia, V., Zydek-Cwick, C. R., andSchlenk, F. 1969. The specificity ofS-adenosylmethionine derivatives in methyl transfer reactions.J. Biol. Chem. 244:4499–4509.
Baudry, M., Chast, F., andSchwartz, J. C. 1973. Studies onS-adenosylhomocysteine inhibition of histamine transmethylation in brain.J. Neurochem. 20:13–21.
Coward, J. K., D'Urso-Scott, M. andSweet, W. D. 1972. Inhibition of catechol-O-methyltransferase byS-adenosylhomocysteine andS-adenosylhomocysteine sulfoxide, a potential transition-state analog.Biochem. Pharmacol. 21:1200–1203.
Lin, R. S., andNarasimhachari, N. 1975.N-methylation of 1-methyltryptamines by indolethylamine-N-methyltransferase.Biochem. Pharmacol. 24:1239–1240.
Pegg, A. E. 1971. Studies on inhibitors of mamalian tRNA methylases.FEBS Letters 16:13–16.
Glick, J. M., Ross, S., andLeBoy, P. S. 1975.S-adenosylhomocysteine inhibition of three purified tRNA methyltransferases from rat liver.Nucleic Acids Res. 2:1639–1651.
Deguchi, T., andBarchas, J. 1971. Inhibition of transmethylation of biogenic amines byS-adenosylhomocysteine.J. Biol. Chem. 246:3175–3181.
Reiner, L., Misani, F., andWeiss, P. 1950. Studies on nitrogen trichloride treated prolamines. VI. Suppression of the development of convulsions with methionine.Arch. Biochem. 25:447–454.
Lodin, A., andKolousek, J. 1958. The effect of some amino acids on the neurotoxic action of methionine sulfoximine.Physiol. Bohemosl. 7:87–94.
Ordonez, L. A., andWurtman, R. J. 1973. Methylation of exogenous 3,4-dihydroxyphenylalanine (l-dopa)—Effects on methyl group metabolism.Biochem. Pharmacol. 22:134–137.
Taylor, K. M., andRandall, P. K. 1975. Depletion ofS-adenosyl-l-methionine in mouse brain by antidepressive drugs.J. Pharmacol. Exp. Ther. 194:303–310.
Lombardini, J. B., andTalalay, P. 1973. Effects of inhibitors of adenosine triphosphate:l-methionineS-adenosyltransferase on levels ofS-adenosyl-l-methionine andl-methionine in normal and malignant mammalian tissues.Molec. Pharmacol. 9:542–560.
Zand, R., Sellinger, O. Z., Water, R., andHarris, R. 1974. α-Aminocyclic and bicyclic alkane carboxylic acids: Differential effects on selected amino acids of rat brain cortex.J. Neurochem. 23:1201–1206.
Glowinski, J., andIversen, L. L. 1966. Regional studies of catecholamines in rat brain. I. The disposition of [H3]norepinephrine, [H3] dopamine and [H3] dopa in various regions of the brain.J. Neurochem. 13:655–669.
de la Haba, G., andCantoni, G. L. 1958. The enzymatic synthesis ofS-adenosyl-l-homocysteine from adenosine and homocysteine.J. Biol. Chem. 234:603–608.
Awwad, H. K., andAdelstein, S. J. 1966. A quantitative method for the determination of the specific radioactivity of sulfur-containing amino acids separated by paper chromatography.Anal. Biochem. 16:433–437.
Salvatore, F., Utili, R., Zappia, V., andShapiro, S. K. 1971. Quantitative analysis ofS-adenosylmethionine andS-adenosylhomocysteine in animal tissues.Anal. Biochem. 41:16–28.
Shapiro, S. K., andEhninger, D. J. 1966. Methods for the analysis and preparation of adenosylmethionine and adenosylhomocysteine.Anal. Biochem. 15:323–333.
Finkelstein, J. D., andHarris, B. 1973. Methionine metabolism in mammals: synthesis ofS-adenosylhomocysteine in rat tissues.Arch. Biochem. Biophys. 159:160–165.
Gaull, G. E., andGaitonde, M. K. 1967. A procedure for the quantitative analysis of the sulphur amino acids of rat tissues.Biochem. J. 102:959–975.
Walker, R. D., andDuerre, J. A. 1975.S-adenosylhomocysteine metabolism in various species.Can. J. Biochem. 53:312–319.
Poulton, J. E., andButt, V. S. 1976. Purification and properties ofS-adenosyl-l-homocysteine hydrolase from leaves of spinach beet.Arch. Biochem. Biophys. 172:135–142.
Finkelstein, J. D., andHarris, B. 1975. Methionine metabolism in mammals:S-adenosylhomocysteine hydrolase in rat intestinal mucosa.Arch. Biochem. Biophys. 171:282–286.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., andRandall, R. J. 1951. Protein measurement with Folin phenol reagent.J. Biol. Chem. 193:265–275.
Porcher, W., andHeller, A. 1972. Regional development of catecholamine biosynthesis in rat brain.J. Neurochem. 19:1917–1930.
Duerre, J. A., Miller, C. H., andReams, G. G. 1969. Metabolism ofS-adenosyl-l-homocysteinein vivo by the rat.J. Biol. Chem. 244:107–111.
Thoa, N. B., Weise, V. K., andKopin, I. J. 1972. Effect ofl-dihydroxyphenylalanine on methylation of3H-norepinephrine and3H-histamine.Biochem. Pharmacol. 21:2345–2350.
Chalmers, J. P., Baldessarini, R. J., andWurtman, R. J. 1971. Effects ofl-DOPA on norepinephrine metabolism in the brain.Proc. Natl. Acad. Sci. 68:662–666.
Ghittoni, N. E., Ohlsson, W. G., andSellinger, O. Z. 1970. The effect of methionine on the regional and intracellular disposition of [3H]-methionine sulfoximine in the rat brain.J. Neurochem. 17:1057–1068.
Schatz, R. A., Harris, R., andSellinger, O. Z. 1976. The effect of methionine on uptake distribution and binding of the convulsant methionine sulfoximine in the rat.Neurochem. Res. 1:53–63.
Baldessarini, R. J., andKarobath, M. 1972. Effects ofl-DOPA andl-3-O-methyl-DOPA on uptake of [3H]l-methionine by synaptosomes.Neuropharmacol. 11:715–720.
Ghittoni, N. E., andSellinger, O. Z. 1970. Cerebral methionine and cysteine levels in rats after injection of the convulsant methionine sulfoximine.Pharmacol. Res. Comm. 2:117–120.
Author information
Authors and Affiliations
Additional information
Supported by USPHS, NINCDS grant NS-06294.
Rights and permissions
About this article
Cite this article
Schatz, R.A., Vunnam, C.R. & Sellinger, O.Z. S-Adenosyl-l-homocysteine in brain. Neurochem Res 2, 27–38 (1977). https://doi.org/10.1007/BF00966019
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00966019