Homocysteine-Induced Oxidative Damage: Mechanisms and Possible Roles in Neurodegenerative and Atherogenic Processes Elke Schlüssel3, Gudrun Preibischa, S

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Homocysteine-Induced Oxidative Damage: Mechanisms and Possible Roles in Neurodegenerative and Atherogenic Processes Elke Schlüssel3, Gudrun Preibischa, S Homocysteine-Induced Oxidative Damage: Mechanisms and Possible Roles in Neurodegenerative and Atherogenic Processes Elke Schlüssel3, Gudrun Preibischa, S. Piitterb and E. F. Elstnera a Lehrstuhl für Phytopathologie, Abt. für Angewandte Biochemie, Technische Universität München, D-85350 Weihenstephan, Bundesrepublik Deutschland b Fa. Medice, D-58638 Iserlohn, Bundesrepublik Deutschland Z. Naturforsch. 50c, 699-707 (1995); received March 27/June 14, 1995 Sulfur Amino Acids, Copper, Iron, Oxidation, Pyridoxalphosphate Increased blood plasma concentrations of the sulphur amino acid homocysteine (“homo- cysteinemia”) have been brought into context with neurodegenerative and arteriosclerotic symptoms and diseases. We recently reported on biochemical model reactions on the prooxidative activity of homo­ cysteine including the desactivation of Na+/K+-ATPases and hemolysis of erythrocytes (Prei- bisch et al., 1993). In this communication we extend our model reactions including the oxida­ tion of methionine, metabolization of pyridoxalphosphate and dihydroxyphenylalanine, desactivations of transaminases and peroxidation of low density lipoprotein. Introduction 1980; Youngman et al, 1982; Youngman and The biosynthesis of methyl group donors such Elstner, 1985; Elstner et al, 1980) we reported that as S-adenosyl-methionine (SAM) and of cysteine methionine in the presence of pyridoxalphosphate (Cys) are essential for the synthesis of methylated is fragmented by certain strong oxidants yielding elements of cell membrane structures such as ethene. This reaction proved as a sensitive indica­ phosphatidylcholine and of antioxidants such as tor for the production of OH-type radicals. The S-methyl-a-ketobutyric acid (KMB), taurin and transamination product of Met, S-methyl-a-keto- glutathione. These central functions are warranted butyric acid (KMB) is a much less specific but very by the homeostasis of methionine metabolism sensitive indicator for the generation of a wide keeping the overall cellular antioxidative system variety of oxygen radicals including Cys or HC in at high fidelity. If this system is out of balance, the presence of copper or iron ions (Preibisch a vast amount of pathological processes may be et al, 1993). In the absence of PyP no ethene is induced mainly concerning nervous disorders and released from Met by certain biological systems atheromatous developments. Homocysteine (HC) such as membraneous oxidoreductases in the as one member in this amphibolic process, how­ presence of autoxidizable redox cyclers or by ever, posseses prooxidative functions which are NAD(P)H oxidases. Methionine (Met) in combi­ biochemically distinct to the reactivities of cys­ nation with pyridoxalphosphate (PyP) or KMB act teine (Preibisch et al, 1993; Preibisch and Elstner, as scavengers of strong oxidants such as the OH- 1994). As recently reported, the pyridoxalphos- radical. Thus, the conversion of homocysteine into phate-glutamate Schiff-base has strongly antioxi­ methionine catalyzed by cobalamine (vitamin B12) dative properties preventing damage by organic in cooperation with folic acid clearly shifts a pro­ hydroperoxides (Meyer et al, 1992). In earlier oxidative towards an antioxidative situation. Vita­ papers (Konze and Elstner, 1976; Saran et al, min B 6 (PyP) both catalyzes the synthesis of KMB as well as the reactivity of methionine as radical scavenger. Thus, the vitamins folic acid and B 12 Abbreviations: Cys, cysteine; HC, homocysteine; HCTL, indirectly act as antioxidants by removing homo­ homocysteinethiolactone; Cu, copper; KMB. 4-methyl- cysteine and producing methionine, whereas PyP thio-2-oxobutanoic acid; Met, methionine; PyP, pyrid­ oxal phosphate; LDL, low density lipoprotein; TA, both in the presence and absence of methionine is transaminase; DOPA, dihydroxyphenylalanine. an effective antioxidant. In this communication we Reprint requests to Prof. Dr. E. F. Elstner. present experimental evidence that HC in the Telefax: 08161-714538. presence of copper or iron ions (see Discussion) 0939-5075/95/0900-0699 $ 06.00 © 1995 Verlag der Zeitschrift für Naturforschung. All rights reserved. 700 E. Schlüssel et al. ■ Oxidative Damage by Homocysteine destroys or alters biomolecules such as transami­ graphically after a 45-min incubation at 37 °C. The nases (TA), dihydroxyphenylalanine (DOPA) or final concentrations, unless otherwise indicated in low density lipoprotein (LDL) which are actively the legends, were 1.0 mM for Met and PyP, 1.0 mM involved in the above mentioned diseases. Homo­ for the metal ions and 0.5 mM for the hydrogen cysteine and methionine metabolism is tightly con­ peroxide. nected and plays a crucial role in a large variety To test the influence of Cys, HC and HCTL on of diseases. An outline of this connection including methionine fragmentation the substances (0.01 up the mentioned damaging reactions as well as their to 2 mM final concentration) were added before counterbalance is presented in Fig. 1. reaction start with metal ions and H 20 2 solu tion . Materials and Methods Assays for transaminase activity Chemicals and Biochemicals For spectrophotometric determination of trans­ Chemicals were obtained from SIGMA Chemi­ aminase activities the procedures of Mavrides cal Co. (Munich) in the greatest available purity. (1987) and SIGMA (quality control test procedure Likewise, the enzymes glutamic-oxalacetic trans­ 10/'93; available upon request) were performed in aminase EC 2. 6 .1.1 from porcine heart G-7005, a slightly modified manner: The substrates for the glutamic-pyruvic transaminase EC 2. 6 .1.2 from transaminase and the dehydrogenase were pi­ porcine heart G-8255, malic dehydrogenase EC petted into half micro disposable cuvettes and the 1.1.1.37 from Thermits flavua M-7032, lactic dehy­ reaction was started by adding transaminase solu­ drogenase EC 1.1.1.27 from porcine heart L-2625 tion. The final concentrations of the glutamic-oxal­ and polyphenoloxidase (tyrosinase) EC 1.14.18.1 acetic transaminase assay were 50 mM L-aspartate, from mushroom T-7755 were purchased from 10 mM a-ketoglutarate, 0.2 mM ß-NADH, 2.4 U SIGMA (Munich). malic dehydrogenase and 0.3 U transaminase. For the glutamic-pyruvic transaminase assay 200 mM M et/PyP-system D,L-alanine, 10 mM a-ketoglutarate, 0.2 mM ß- Met and PyP were allowed to react at room tem­ NADH, 7.5 U lactic dehydrogenase and 0.1 U perature in 0.2 m phosphate-bufferd solution (pH transaminase were added. (Unit definition: One 7.4) for 10 min forming the Schiff-base. Then, Fe2+ International Unit (U) is defined as that amount or Cu2+ ions (FeCl 2 -4H20 or CuS0 4 -5H20 dis­ of enzyme that will form 1 (.imol of glutamate per solved in aqua bidest.) and H 20 2 were added. minute at pH 7.5 and 25 °C.). After stirring the Ethene production was measured gaschromato- decrease in absorbance at 340 nm was recorded antioxidant toxicity JCu, Fe KMR homocysteine- antioxidant thiolactone »6 B12 m ethionine homocysteine - cysteine glutathione folate »6 I Cu. Fe | Cu, Fe methionine + pyridoxal slow oxidation rapid oxidation phosphate antioxidant Fig. 1. Methionine-homo- cvsteine metabolism. E. Schlüssel et al. ■ Oxidative Damage by Homocysteine 701 for approximately 15 min to obtain the maximum determined by agarose gel electrophoresis (ac­ linear reaction rate (A/l/min = activity). cording to Cooper, 1983). To study the influence of the test substances (Cys, HC, HCTL) on enzyme activity a preincuba­ Results tion of the transaminases with the sulphur com­ The combination of both Met and PyP is appa­ pounds at 37 °C for 15 min preceeded the addition rently producing an antioxidant rapidly reacting to the reaction mixture. Activities were compared with the potent oxidant of the OH' type, including as percentages of control activity. transition metal-oxygen complexes of the “Fen- ton-type” i.e. Fe2+ in the presence of a peroxide. Reactions with o-quinone products from We assayed this reaction with respect to the effects PPO-catalyzed dihyroxyphenylalanine (DOPA) of iron or copper ions, which are under increasing oxidation discussion as initiators and/or cofactors of the de­ A mixture containing 9.6 mM DOPA, 0.8 mM velopments of neurodegenerative (Youdim and Cys/HC/HCTL respectively and 783 U poly- Lavie, 1994) and atherosclerotic diseases (Meyer phenoloxidase in 0.2 m phosphate buffered solu­ et al., 1992; Kögl et al., 1994; Lupo et al., 1994), tion (pH 6.0) was allowed to react 2.5 - 5 - 10 - where the sulphur containing amino acid, methio­ 20 - 30 - 45 - 60 min, respectively, then the reac­ nine, seems to be in the focus of such oxidative tion was stopped by adding an equal volume of destructions (Preibisch and Elstner, 1994; Gilman methanol. Particles were removed by a 10 min et al., 1993). centrifugation at 1000 xg in an Eppendorf-centri- fuge. After dilution 1 : 5 with the reaction buffer, 1) Reactions with methionine and HPLC analysis was performed. A reversed phase pyridoxalphosphate column Hypersil ODS (particle size 5 |.im, pore In the presence of either iron2+ or copper2+ ions, size 100 A) was used. The flow rate was 1 ml the release of ethene from methionine was tested 50 mM phosphate buffer pH 2.4 / min and products as to the effects of cysteine, homocysteine, or were detected at 254 nm. homocysteine thiolactone. As shown in Fig. 2, in the presence of hydrogen Oxidation o f low density lipoprotein peroxide and either iron or copper, increasing LDL from human venous blood was subjected amounts of ethene are released from increasing to oxidation by 2.5 and 5 ^im Cu 2+ respectively. concentrations of Met in the test system. This reac­ Dieneconjugation was measured spectrophoto- tion is inhibited by PyP in the copper system and metrically by monitoring increase in absorbance at to a much lesser extent in the slower reacting iron 234 nm, changes in electrophoretic mobility were system (Fig. 2). cu <D -Q _Q 6000 co .{2 6000 Ar" \ « o Iron / Hydrogen peroxide - system ro 03 > \ a a Copper / Hydrogen peroxide - system > Q) 5000 5000 CL C o c ▲ o 0- E .2 4000 4000 E - CL SZ Ä ^ <U 3000 3000 a) E JZ§ T-° 2000 2000 LLJ £ Fig.
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