Pathways of Ethanol Metabolism in Perfused Rat Liver

  • Ronald G. Thurman
  • William R. McKenna
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 56)


Traditionally, ethanol metabolism is a function attributed solely to the hepatic enzyme alcohol dehydrogenase (ADH) (1). Whereas the importance of the liver as the primary organ of ethanol metabolism remains unchallenged (2), recent years have seen the accumulation of evidence indicating that enzyme systems other than alcohol dehydrogenase participate in the metabolism of ethanol (3, 4,5). However, the identity of the enzyme(s) responsible for ADHindependent ethanol metabolism is a subject of great controversy (6,7,8). Evidence has been presented in favor of the catalase-hydrogen peroxide complex (4,5) and, in turn, for the so-called Microsomal Ethanol Oxidizing System (MEOS) (3,9) as additional hepatic ethanol-oxidizing systems. Extrapolations from inhibition studies performed in vitro to in vivo situations have created a great deal of confusion concerning the quantitative role of ADH as well as of other possible pathways. The present study will both review the problems involved in the evaluation of the pathways of ethanol metabolism and describe a combination of experimental techniques which make it clear that ethanol is metabolized principally by alcohol dehydrogenase at low ethanol concentrations (5). On the other hand, at high ethanol concentrations, catalase participates in ethanol metabolism to a significant degree.


Alcohol Dehydrogenase Perfuse Liver Liver Slice Ethanol Oxidation Pyridine Nucleotide 
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.


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  1. 1.
    Lundsgaard, E., Alcohol oxidation as a function of the liver. Compt. Rend. Tray. Lab. Carlsberg, 22: 333–345, 1938.Google Scholar
  2. 2.
    Goodman, L.S. and Gilman, A.G., The Pharmacological Basis of Therapeutics. The Macmillan Co, New York, 1965.Google Scholar
  3. 3.
    Lieber, L.S. and DeCarli, L.M., Hepatic microsomal ethanol oxidizing system. J. BioZ. Chem., 245: 2505–2512, 1970.Google Scholar
  4. 4.
    Keilin, D. and Hartree, E.F., Properties of catalase. Catalysis of coupled oxidation of alcohols, Biochem. J., 39: 293–301.Google Scholar
  5. 5.
    Thurman, R.G., McKenna, W.R., Brentzel, H.J. Jr. and Hesse, S., Significant pathways of ethanol metabolism. Federation Proceedings, In Press, 1974.Google Scholar
  6. 6.
    Thurman, R.G., Hesse, S. and Scholz, R., The role of NADPH-dependent hydrogen peroxide formation and catalase in hepatic microsomal ethanol oxidation. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance, (eds.), Academic Press, 257–270, 1974.Google Scholar
  7. 7.
    Roach, M.K., Reese, W.N., Creaven, P.J., Ethanol oxidation in the microsomal fraction of rat liver. Biochem. Biophysics Res. Comm., 36: 596–602, 1969.CrossRefGoogle Scholar
  8. 8.
    Isselbacher, K.J. and Carter, E.A., Ethanol oxidation by liver microsomes. Evidence against a separate and distinct enzyme system. Biochem. Biophysics. Res. Comm., 39: 530–537, 1970.CrossRefGoogle Scholar
  9. 9.
    Lieber, C.S., Teschke, R., Hasamura, Y. and DeCarli, L.M., Interaction of ethanol with liver microsomes. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance (eds.), Academic Press, 243–256, 1974.Google Scholar
  10. 10.
    Ehrenberg, A. and Dalziel, K., Molecular weight of horse liver alcohol dehydrogenase. Acta Chem. Scand., 12: 465–471, 1958.CrossRefGoogle Scholar
  11. 11.
    Bonnichsen, R. and Wassen, A.M., Crystalline alcohol dehydrogenase from horse liver. Arch. Biochem., 18: 361–369, 1948.PubMedGoogle Scholar
  12. 12.
    Shore, J. and Theorell, H., A kinetic study of ternary complexes in the mechanism of action of liver alcohol dehydrogenase. Arch. Biochem. Biophys., 116: 255–260, 1966.PubMedCrossRefGoogle Scholar
  13. 13.
    Lehninger, A.L., Phosphorvlation coupled to oxidation of dihydrodiphosphopyridine nucleotide. J. BioZ. Chem., 236: 345–359, 1951.Google Scholar
  14. 14.
    Tottmar, S.O.C., Petterson, H. and Kiessling, K.H., Aldehyde dehydrogenases in rat liver. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance (eds.), Academic Press, 147–160, 1974.Google Scholar
  15. 15.
    Grunnet, N., Quistorff, B. and Theiden, H.I.O., Rate-limiting factors in ethanol oxidation by isolated rat liver parenchymal cells. Eur. J. Biochem., 40: 275–282, 1973.PubMedCrossRefGoogle Scholar
  16. 16.
    Purvis, J.C. and Lowenstein, J.M., The relation between intra-and extra-mitochondrial pyridine nucleotides. J. Biol. Chem., 236: 2794–2803, 1961.PubMedGoogle Scholar
  17. 17.
    Borst, P., In: Functionelle and Morphologische Organization der Zelle. Karlson, P., (ed.), Springer-Verlag, Heidelberg, 137, 1963.Google Scholar
  18. 18.
    Williamson, J.R., Meijer, A.J. and Ohkawa, K., Interrelations between anion transport, ureogenesis and guconeogenesis in isolated rat liver cells. In: Regulation of Hepatic Metabolism. F. Underquist, N. Tygstrup and J. Thaysen (eds.), Munskaard, Copenhagen, 537–559, In Press, 1974.Google Scholar
  19. 19.
    Bucher, Th. and Klingenberg, M., Wege des Wasserstoffs in der lebendigen Organisation. Angew. Chem., 70: 552–557, 1958.CrossRefGoogle Scholar
  20. 20.
    Estabrook, R.W. and Sactors, B. a-Glycerophosphate oxidase of flight muscle mitochonria. J. BioZ. Chem., 233: 1014–1019, 1958.Google Scholar
  21. 21.
    Williamson, J.R., Scholz, R., Thurman, R.G. and Chance, B. Transport of reducing equivalents across the mitochondrial membrane in rat liver. In: The Energy Level and Metabolic Control in Mitochondria. S. Papa, J.M. Tager, E. Quagliariello and E.C. Slater (eds.), Adriatica Editrice, Bari, 411–429, 1969.Google Scholar
  22. 22.
    Scholz, R., Thurman, R.G., Williamson, J.R., Chance, B. and Bucher, Th. Flavin and pyridine nucleotide oxidation-reduction changes in perfused rat liver. J. BioZ. Chem., 244: 2317–2324, 1969.Google Scholar
  23. 23.
    Williamson, J.R., Scholz, R., Browning, E.T., Thurman, R.G. and Fukami, M.H. Metabolic effects of ethanol in perfused rat liver. J. BioZ. Chem., 244: 5044–5054, 1969.Google Scholar
  24. 24.
    McCaffrey, T.B. and Thurman, R.G. Mechanism of the adaptive increase in ethanol utilization due to chronic prior treatment with alcohol. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance (eds.), Academic Press, 483–492, 1974.Google Scholar
  25. 25.
    Videla, L. and Israel, Y. Factors that modify the metabolism of ethanol in rat liver and adaptive changes produced by its chronic administration. Biochem. J., 118: 275–281, 1970.PubMedGoogle Scholar
  26. 26.
    Madison, L.L., Lochner, A., Wolff, J. Ethanol-induced hypoglycemia: Mechanism of suppression of hepatic gluconeogenesis. Diabetes, 16: 252–258, 1967.PubMedGoogle Scholar
  27. 27.
    Plapp, B. Rate-limiting steps in ethanol metabolism and approaches to changing these rates biochemically. This volume.Google Scholar
  28. 28.
    Hassinen, I.E. and Ylikahri, R.H. Mixed function oxidase and ethanol metabolism in perfused rat liver. Science, 176: 1435–1437, 1972.PubMedCrossRefGoogle Scholar
  29. 29.
    Widmark, E.M.P. Die theoretischen Grundlagen and die praktische Verwendbarkeit der gericht-medizinische Alkcholbestimmung. Urban and Schwarzenberg, Berlin, 1932.Google Scholar
  30. 30.
    Pietruszko, R. Mammalian liver alcohol dehydrogenases. This volume.Google Scholar
  31. 31.
    Laser, H. Peroxidatic activity of catalase. J. Biochem., 61: 122–127, 1955.Google Scholar
  32. 32.
    Kinard, F.W., Nelson, G.H. and Hay, M.G. Catalase activity and ethanol metabolism in the rat. Proc. Soc. Exptl. Biol. Pled., 92: 772–773, 1956.Google Scholar
  33. 33.
    Nelson, G.H., Kinard, F.W., Hull, J.C. and Hay, M.G. Effect of aminotriazole on alcohol metabolism and hepatic enzyme activities in several species. Quart. J. Studies AZc., 18: 343–348, 1957.Google Scholar
  34. 34.
    Sies, H. and Chance, B. The steady state level of catalase compound I in isolated hemoglobin free perfused rat liver. Fed. Europ. Biochem. Socs. Letters, 11: 172–176, 1970.CrossRefGoogle Scholar
  35. 35.
    Oshino, N., Jamieson, D. and Chance, B. The characteristics of the peroxidatic reaction of catalase in ethanol oxidation. Biochem. J.,Submitted for publication.Google Scholar
  36. 36.
    Thurman, R.G., Ley, H.G. and Scholz, R. Hepatic microsomal ethanol oxidation. Eur. J. Biochem., 25: 420–430, 1972.PubMedCrossRefGoogle Scholar
  37. 37.
    Boveris, A., Oshino, N. and Chance, B. The cellular production of hydrogen peroxide. Biochem. J., 128: 617–630, 1972.PubMedGoogle Scholar
  38. 38.
    Oshino, N., Chance, B., Sies, H. and Bucher, Th. The role of hydrogen peroxide generation in perfused rat liver and the reaction of catalase compound I and hydrogen donors. Arch. Biochem. Biophys., 154: 117–131, 1973.PubMedCrossRefGoogle Scholar
  39. 39 Chance, B., Oshino, N., Sugarno, T. and Jamieson, D. Role of catalase in ethanol metabolism. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance (eds.), Academic Press,1974.Google Scholar
  40. 40.
    Thurman, R.G. and McKenna, W.R. Activation of ethanol utilization in perfused livers from normal and ethanol pretreated rats. Hoppe-Seyler’s Z. Physiol. Chem., 355: 335–340, 1974.CrossRefGoogle Scholar
  41. 41.
    McKenna, W.R. and Thurman, R.G. Activation of ethanol utilization in perfused livers from normal and ethanol pretreated rats. Fed. Proc., Abs., 33: 554, 1974.Google Scholar
  42. 42.
    Roach, M. Microsomal ethanol oxidation: Activity in vitro and in vivo This volume.Google Scholar
  43. 43.
    Thurman, R.G. and Scholz, R. The role of hydrogen peroxide and catalase in hepatic microsomal ethanol oxidation. Drug Met. Dispos.. I: 441–448, 1973.Google Scholar
  44. 44.
    DeCarli, L.M. and Lieber, C.S. Fatty liver in the rat after prolonged intake of ethanol with a nutritionally adequate new liquid diet. J. Nutrition, 91: 331–336, 1967.Google Scholar
  45. 45.
    Porta, E.A., Cesar, L.A. and Gomez-Dumm, L.A. A new experimental approach in the study of chronic alcoholism I. Effects of high alcohol intake in rats fed a commercial laboratory diet. Lab. Invest., 18: 352–364, 1968.PubMedGoogle Scholar
  46. 46.
    Israel, Y., cited by Lundquist, F. Metabolism of alcohol, In Biological Basis of Alcoholism. Israel, Y. and Mardonnes, J. (eds.) Wiley-Interscience, p. 15, New York, 1971.Google Scholar
  47. 47.
    Theorell, H. and Chance, B. Studies on liver alcohol dehydrogenases II. The kinetics of the compound of horse liver alcohol dehydrogenase and reduced diphosphopyridine nucleotide. Acta Chem. Scand., 5: 1127–1144, 1951.CrossRefGoogle Scholar
  48. 48.
    Israel, Y., Bernstein, J. and Videla, L. On the mechanism of the changes in liver oxidative capacity produced by chronic alcohol ingestion. In: Alcohol and Aldehyde Metabolizing Systems. R.G. Thurman, T. Yonetani, J.R. Williamson and B. Chance, (eds.), Academic Press, 493–509, 1974.Google Scholar
  49. 49.
    Thurman, R.G. and McKenna, W.R. Interrelationship between the adaptive increase in ethanol utilization due to chronic pretreatment with ethanol and energy metabolism. Fed. Proc., Abs 33: 1387, 1974.Google Scholar
  50. 50.
    Autor, A.P., Kaschnitz, R.M., Heidema, J., Coon, M.J. Sedimentation and other properties of the reconstituted liver microsomal mixed-function oxidase system containing cytochrome p-450, TPNH-cytochrome p-450 reductase and phosphatidylcholine. Mol. Pharmacol,In press.Google Scholar
  51. 51.
    Gupta, N.K. and Robinson, W.G. Coupled oxidation-reduction activity of liver alcohol dehydrogenase. Biochem. Biophys. Acta, 118: 431–434, 1966.PubMedGoogle Scholar
  52. 52.
    Nash, T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem. J., 55: 416–421, 1953.PubMedGoogle Scholar
  53. 53.
    Cochin, J. and Axelrod, J. Biochemical and pharmacological changes in the rat following chronic administration of morphine, nalorphine and normorphine. J. Pharmacol. Exp. Thera., 125: 105–110, 1959.Google Scholar
  54. 54.
    Lu, A.Y.H., Junk, K.W., Coon, M. J. Resolution of the cytochrome p-450-containing hydroxylation system of liver microsomes into three components. J. Biol. Chem., 244: 3711–3731, 1968.Google Scholar
  55. 55.
    Lu, A.Y.H. and Coon, M.J. Role of hemoprotein p-450 in fatty acid hydroxylation in a soluble enzyme system from liver microsomes. J. BioZ. Chem., 243: 1331–1332, 1968.Google Scholar
  56. 56.
    Lieber, C.S. Metabolic derangement induced by alcohol. Ann. Rev. Med., 18: 35–54, 1967.PubMedCrossRefGoogle Scholar
  57. 57.
    Grunnet, N., Oxidation of acetaldehyde by rat liver mitochondria in relation to ethanol oxidation and the transport of reducing equivalents across the mitochondrial membraine. Europ. J. Biochem., 35: 236–243, 1973.PubMedCrossRefGoogle Scholar
  58. 58.
    Marjanen, L., Intracellular localization of aldehyde dehydrogenase in rat liver. Biochem. J., 197: 633–639, 1972.Google Scholar
  59. 59.
    Hawkins, R.D. and Kalant, H., The metabolism of ethanol and its metabolic effects. Pharmacol. Rev., 24: 67–138, 1972.PubMedGoogle Scholar
  60. 60.
    Watkins, W.D., Goodman, J.I. and Tephley, T.R., Inhibition of methanol and ethanol oxidation by pyrazole in the rat and monkey in vivo. Mol. Pharmcology, 6: 567–572, 1970.Google Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • Ronald G. Thurman
    • 1
  • William R. McKenna
    • 1
  1. 1.Johnson Research FoundationUniversity of Pennsylvania School of MedicineUSA

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