Skip to main content

Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress: a hypothesis

  • Miklós Ghyczy (a1) and Mihály Boros (a2)

Reductive stress, characterised by an increased NADH:NAD+ ratio, may be as common and as important a consequence of redox imbalance as oxidative stress. It may also be an important predisposing cause of the generation of reactive oxygen species. Considerable experimental and indirect clinical evidence suggests that protection against reductive stress depends on biomolecules with electrophilic methyl groups (EMG) such as S-adenosylmethionine, betaine, carnitine and phosphatidylcholine. Pathological processes leading to reductive stress and their relief by such protective agents is reviewed and the proposed molecular mechanism is outlined. These and other EMG-containing biomolecules are part of the daily diet and may represent an important control system for redox balance.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress: a hypothesis
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress: a hypothesis
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress: a hypothesis
      Available formats
Corresponding author
*Corresponding author: Dr Miklós Ghyezy, fax +49 221 509 2816, email
Hide All
Aleynik SI, Leo MA, Ma X, Aleynik MK & Lieber CS (1997) Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis. Journal of Hepatology 27, 554561.
Arias-Diaz J, Vara E, Garcia C, Villa N, Rodriguez JM, Ortiz P & Balibrea JL (1996) S-adenosylmethionine protects hepatocytes against the effects of cytokines. Journal of Surgical Research 62, 7984.
Balazsovits JA, Mayer LD, Bally MB, Cullis PR, McDonell M, Ginsberg RS & Falk RE (1989) Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemotherapy and Pharmacology 23, 8186.
Barak AJ, Beckenhauer HC, Badakhsh S & Tuma DJ (1997) The effect of betaine in reversing alcoholic steatosis. Alcohol Clinical and Experimental Research 21, 11001102.
Barak A, Beckenhauer HC, Junnila M & Tuma DJ (1993) Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clinical and Experimental Research 17, 552555.
Barak AJ, Beckenhauer HC & Tuma DJ (1994) S-adenosylmethionine generation and prevention of alcoholic fatty liver by betaine. Alcohol 11, 501503.
Bertelli A, Cerrati A, Giovannini L, Mian M, Spaggiari P & Bertelli AA (1993) Protective action of L-carnitine and coenzyme Q10 against hepatic triglyceride infiltration induced by hyperbaric oxygen and ethanol. Drugs Experimental and Clinical Research 19, 6568.
Blusztajn JK (1998) Choline, a vital amine. Science 281, 794795.
Broderick TL, Quinney HA, Barker CC & Lopaschuk GD (1993) Beneficial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation. Circulation 87, 972981.
Broderick TL, Quinney HA & Lopaschuk GD (1995) L-carnitine increases glucose metabolism and mechanical function following ischaemia in diabetic rat heart. Cardiovascular Research 29, 373378.
Cha YS & Sachan DS (1995) Acetylcarnitine-mediated inhibition of ethanol oxidation in hepatocytes. Alcohol 12, 289294.
Corbucci GG, Menichetti A, Cogliatti A, Nicoli P & Ruvolo C (1992) Metabolic aspects of acute tissue hypoxia during extracorporeal circulation and their modification induced by L-carnitine treatment. International Journal of Clinical Pharmacology Research 12, 149157.
Diplock AT, Aggett PJ, Aswell M, Bornet F, Fern EB & Roberfroid MB (1999) Scientific concepts of functional foods in Europe: consensus document. British Journal of Nutrition 81, S1S27.
Diplock AT, Charleux J-L, Crozier-Willi G, Kok FJ, Rice-Evans C, Roberfroid M, Stahl W & Vina-Ribes J (1998) Functional food science and defence against reactive oxidative. British Journal of Nutrition 80, S77S112.
Duan J & Karmazyn M (1990) Protection of the reperfused ischemic isolated rat heart by phosphatidylcholine. Journal of Cardiovascular Pharmacology 15, 163171.
Duan J & Moffat MP (1990) Protective effects of phosphatidylcholine against mechanisms of ischemia and reperfusion-induced arrhythmias in isolated guinea pig ventricular tissues. Naunyn-Schmiedeberg′s Archives of Pharmacology 342, 342348.
Duce AM, Ortíz P, Cabrero C & Mato JM (1988) S-adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis. Hepatology 8, 6568.
Dunjic BS, Axelson J, Ar′Rajab A, Larsson K & Bengkmark S (1993) Gastroprotective capability of exogenous phosphatidylcholine in experimentally induced chronic gastric ulcers in rats. Scandinavian Journal of Gastroenterology 28, 8994.
Dunne JB, Davenport M, Williams R & Tredger JM (1994) Evidence that S-adenosylmethionine and N-acetylcysteine reduce injury from sequential cold and warm ischemia in the isolated perfused rat liver. Transplantation 57, 11611168.
Dunne JB, Piratvisuth T, Williams R & Tredger JM (1997) Treatment of experimental ischemia/reperfusion injury with S-adenosylmethionine: Evidence that donor pretreatment complements other regimens. Transplantation 63, 500506.
Feo F, Pascale R, Garcea R, Daino L, Pirisi L, Frassetto S, Ruggiu ME, Di Padova C & Stramentinoli G (1986) Effect of the variations of S-adenosyl-L-methionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats. Toxicology and Applied Pharmacology 83, 331341.
Fernandez E, Galan AI, Moran D, Gonzalez-Buitrago JM, Munoz ME & Jimenez R (1995) Reversal of cyclosporine A-induced alterations in biliary secretion by S-adenosyl-L-methionine in rats. Journal of Pharmacology and Experimental Therapeutics 275, 442449.
Gabizon A, Meshorer A & Barenholz Y (1986) Comparative long-term study of the toxicities of free and liposome-associated doxorubicin in mice after intravenous administration. Journal of the National Cancer Institute 77, 459469.
Garcia-Ruiz C, Morales A, Colell A, Ballelsta A, Rodes J, Kaplowitz N & Fernandez-Checa JC (1995) Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology 21, 207214.
Garro AJ, McBeth DL, Lima V & Lieber CS (1991) Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome. Alcohol Clinical and Experimental Research 15, 395398.
Gilbert BE, Knight C, Alvarez FG, Waldrep C, Rodarte JR, Knight V & Eschenbacher WL (1997) Tolerance of volunteers to cyclosporine A-dilauroylphosphatidylcholine liposome aerosol. American Journal of Respiration Critical Care Medicine 156, 17891793.
Giovannini L, Palla R, Bertelli AA, Migliori M, Panichi V, Andreini B, De Pietro S & Bertelli A (1996) Cyclosporine nephrotoxicity evaluated by tissue calcium deposition and tubular enzymes is prevented by L-propionylcarnitine in isolated perfused rat kidney. Transplantation Proceedings 28, 31223125.
Hensley K, Kotake Y, Sang H, Pye QN, Wallis GL, Kolker LM, Tabatabaie T, Stewart CE, Konishi Y, Nakae D & Floyd RE (2000) Dietary choline restriction causes complex I dysfunction and increased H2O2 generation in liver mitochondria. Carcinogenesis 21, 983989.
Jaeschke H, Kleinwaechter C & Wendel A (1992) NADH-dependent reductive stress and ferritin-bound iron in allyl alcohol-induced lipid peroxidation in vivo: the protective effect of vitamin E. Chemical Biology Interactions 81, 5768.
Khan S & O′Brien PJ (1995) Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state. Biochimica et Biophysica Acta 1269, 153161.
Laudanno OM, Finkelstein D & Capdepon E (1987) Complete cytoprotective action on the gastroduodenal mucosa induced by SAM against damage provoked by ethanol in man. Panminerva Medica 29, 7578.
Leyck S, Dereu N, Etschenberg E, Ghyczy M, Graf E, Winkelmann J & Parnham MJ (1985) Improvement of the gastric tolerance of non-steroidal antiinflammatory drugs by polyene phosphatidylcholine (Phospholipon 100). European Journal of Pharmacology 117, 3542.
Lichtenberger LM, Graziani LA, Dial EJ, Butler BD & Hills BA (1982) Role of surface-active phospholipids in gastric cytoprotection. Science 219, 13271329.
Lieber CS (1997) Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. Advances in Pharmacology 38, 601628.
Lieber CS, Casini A, De Carli LM, Kim CI, Lowe N, Sasaki R & Leo MA (1990 a) S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology 11, 165172.
Lieber CS, De Carli LM, Mak KM, Kim CI & Leo MA (1990 b) Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 12, 13901398.
Lieber CS, Leo MA, Aleynik SI, Aleynik MK & DeCarli LM (1997) Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon. Alcohol Clinical Experimental Research 21, 375379.
Lieber CS, Robins SJ & Leo MA (1994 a) Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine. Alcoholism Clinical and Experimental Research 18, 592595.
Lieber CS, Robins SJ, Li J, De Carli LM, Mak KM, Fasulo JM & Leo MA (1994 a) Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology 106, 152159.
Niknahad H, Khan S & O′Brien PJ (1995) Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation. Chemical Biology Interaction 98, 2744.
Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K & Kagan V (1991) Free radical scavenging is involved in the protective effect of L-propionyl-carnitine against ischemia-reperfusion injury of the heart. Archives of Biochemistry and Biophysics 288, 533537.
Panos MZ, Polson R, Johnson R, Portman B & Williams R (1990) Polyunsaturated phosphatidyl choline for acute alcoholic hepatitis: a double-blind, randomized, placebo-contolled trial. Journal of Gastroenterology and Hepatology 2, 351355.
Poirier LA (1994) Methyl group deficiency in hepatocarcinogenesis. Drug Metabolism Review 26, 185199.
Rhew TH & Sachan DS (1986) Dose-dependent lipotropic effect of carnitine in chronic alcoholic rats. Journal of Nutrition 116, 22632269.
Roman ID, Johnson GD & Coleman R (1996) S-adenosyl-L-methionine prevents disruption of canalicular function and pericanalicular cytoskeleton integrity caused by cyclosporin A in isolated rat hepatocyte couplets. Hepatology 24, 134140.
Sachan DS & Cha YS (1994) Acetylcarnitine inhibits alcohol dehydrogenase. Biochemical Biophysical Research Communications 203, 14961501.
Sachan DS, Rhew TH & Ruark RA (1984) Ameliorating effects of carnitine and its precursors on alcohol-induced fatty liver. American Journal of Clinical Nutrition 39, 738744.
Shinozuka H, Lombardi B, Sell S & Iammarino RM (1978) Early histological and functional alterations of ethionine liver. Cancer Research 38, 10921098.
Soehngen EC, Godin-Ostro E, Fielder FG, Ginsberg RS, Slusher MA & Weiner AL (1987) Encapsulation of indomethacin in liposomes provides protection against both gastric and intestinal ulceration when orally administered to rats. Arthritis Rheumatology 31, 110.
Stäubli A & Boelsterli UA (1998) The labile iron pool in hepatocytes: prooxidant-induced increase in free iron precedes oxidative cell injury. American Journal of Physiology 274, G1031G1037.
Stoffel W, Le Kim D & Tschung TS (1971) A simple chemical method for labelling phosphatidylcholine and sphingomyelin in the choline moiety. Zeitschrift für Physiologische Chemie 352, 10581064.
Storm G, Van Hoesel QG, De Groot G, Kop W, Steerenberg PA & Hillen FC (1989) A comparative study on the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as a bolus, continuous infusion or entrapped in liposomes in the Lou/M Wsl rat. Cancer Chemotherapy and Pharmacology 24, 341348.
Swarm RA, Ashley SW, Soybel DI, Ordway FS & Cheung LY (1987) Protective effect of exogenous phospholipid on aspirin-induced gastric mucosal injury. American Journal of Surgery 153, 4853.
Szelenyi I & Engler H (1986) Cytoprotective role of gastric surfactant in the ethanol-produced gastric mucosal injury of the rat. Pharmacology 33, 199205.
Vara E, Arias-Diaz J, Garcia C, Villa N, Simon C, Ortiz P & Balibrea JL (1994) S-adenosyl-methionine may protect transplanted hepatocytes against the toxic effects of cytokines. Transplantation Proceedings 26, 33643366.
Winter BK, Fiskum G & Gallo LL (1995) Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock. British Journal of Cancer 72, 11731179.
Zeisel SH, Da Costa KA, Franklin PD, Alexander EA, Lamont JT, Sheard NF & Beiser A (1991) Choline, an essential nutrient for humans. FASEB Journal 5, 20932098.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 130 *
Loading metrics...

Abstract views

Total abstract views: 152 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 18th January 2018. This data will be updated every 24 hours.