Lobular Oxygen Gradients: Possible Role in Alcohol-Induced Hepatotoxicity

  • Ronald G. Thurman
  • Sungchul Ji
  • John J. Lemasters


Alcoholic liver disease is a major health problem, and specific therapies are lacking because we still do not understand how alcohol causes liver damage. The purpose of this chapter is to evaluate the evidence for and against the hypothesis that hypoxia is involved in this disease. We shall review hepatic oxygen uptake, ethanol metabolism and adaptations, and hypoxic tissue damage in general briefly.


Oxygen Uptake Alcohol Dehydrogenase Alcoholic Liver Disease Liver Lobule Perfuse Liver 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Thurman, R. G., and Scholz, R., 1969, Mixed-function oxidation in perfused rat liver: The effect of aminopyrine on oxygen uptake, Eur. J. Biochem. 10: 459–467.PubMedCrossRefGoogle Scholar
  2. 2.
    Mitchell, P., 1966, Chemiosmotic coupling in oxidative and photosynthetic phosphorylation, Biol. Rev. 41: 445–502.PubMedCrossRefGoogle Scholar
  3. 2a.
    Schneider, H., Lemasters, J. J., Höchli, M., and Hackenbrock, C. R., 1980, Lipo-some-mitochondrial inner membrane fusion: Lateral diffusion of integral electron transfer components, J. Biol. Chem. 255: 3748–3756.PubMedGoogle Scholar
  4. 3.
    Chance, B., and Williams, G. R., 1955, Respiratory enzymes in oxidative phosphrylation I-V, J. Biol. Chem. 217: 383–438.PubMedGoogle Scholar
  5. 3a.
    Boyer, P. D., Chance, B., Ernst, L., Mitchell, P., Racker, E., and Slater, E. C., 1977, Oxidative phosphorylation and photophorylation, Annu. Rev. Biochem. 46: 955–1026.PubMedCrossRefGoogle Scholar
  6. 3b.
    Lemasters, J. J., 1985, The ATP/oxygen and ATP/site ratios of oxidative phosphorylation: An analysis by nonequilibrium thermodynamics, Comments Molec. Cell. Biophysics (in press).Google Scholar
  7. 3c.
    Grunwald, R., and Lemasters, J. J., 1982, Rate-limitation of mitochondrial oxidative phosphorylation, EBEC Short Rep. 2: 269–270.Google Scholar
  8. 3d.
    Groen, A. K., Wanders, R. J., Westerhoff, H. V., van der Meer, R., and Tager, J. M., 1982, Quantification of the contribution of various steps to the control of mitochondrial respiration, J. Biol. Chem. 257: 2754–2757.PubMedGoogle Scholar
  9. 4.
    Theorell, H., and Chance, B., 1951, Studies on liver alcohol dehydrogenase. II. The kinetics of the compound of horse liver alcohol dehydrogenase and reduced diphosphopyridine nu-cleotide, Acta Chem. Scand. 5: 1127–1144.CrossRefGoogle Scholar
  10. 5.
    Brändén, E.-I., Eklund, H., Zeppezauer, E., Nordström, B., Bowie, J., Söderland, G., and Ohlsson, I., 1974, Three-dimensional structure of the horse liver alcohol dehydrogenase molecule, in: Alcohol and Aldehyde Metabolizing Systems (R. G. Thurman, T. Yonetani, J. R. Williamson, and B. Chance, eds.), pp. 7–21, Academic Press, New York.Google Scholar
  11. 6.
    Williamson, J. R., Scholz, R., Thurman, R. G., and Chance, B., 1969, 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.), pp. 411–429, Adriatica Editrice, Bari.Google Scholar
  12. 7.
    Theorell, H., Nygaard, A. P., and Bonnichsen, R., 1969, On the effect of some heterocyclic compounds on the enzymatic activity of liver alcohol dehydrogenase, Acta Chem. Scand. 23: 255.PubMedCrossRefGoogle Scholar
  13. 8.
    Thurman, R. G., McKenna, W. R., Brentzel, H. J. and Hesse, S., 1975, Significant pathways of hepatic ethanol metabolism, Fed. Proc. Fed. Am. Soc. Exp. Biol. 34: 2075–2081.Google Scholar
  14. 9.
    Madison, L., Lochner, A., and Wolff, J., 1967, Ethanol-induced hypoglycemia. II. Mechanism of suppression of hepatic gluconeogenesis, Diabetes 16: 252–258.PubMedGoogle Scholar
  15. 10.
    Videla, L., and Israel, Y., 1970, Factors that modify the metabolism of ethanol in rat liver and adaptive changes produced by its chronic administration, Biochem. J. 118: 275–281.PubMedGoogle Scholar
  16. 11.
    Williamson, J. R., Scholz, R., Browning, E. T., Thurman, R. G., and Fukami, M. H., 1969, Control mechanisms of gluconeogenesis and ketogenesis. III. Metabolic effects in perfused rat liver, J. Biol. Chem. 244: 5044.PubMedGoogle Scholar
  17. 12.
    Scholz, R., and Nohl, H., 1976, Mechanism of the stimulatory effect of fructose on ethanol oxidation in perfused rat liver, Eur. J. Biochem. 63: 449–458.PubMedCrossRefGoogle Scholar
  18. 13.
    Lumeng, L., Bosron, W. F., and Li, T.-K., 1979, Quantitative correlation of ethanol elimination rates in vivo with liver alcohol dehydrogenase activities in fed, fasted and food-restricted rats, Biochem. Pharmacol. 28: 1547–1551.PubMedCrossRefGoogle Scholar
  19. 14.
    von Wartburg, J. P., and Scharch, P. M., 1968, Atypical human liver alcohol dehydrogenase, Ann. N. Y. Acad. Sci. 151: 936.Google Scholar
  20. 15.
    von Wartburg, J. P., 1971, The metabolism of alcohol in normals and alcoholics: Enzymes, in: The Biology of Alcoholism, Vol. 1 (B. Kissin and H. Begleiter, eds.), pp. 63–102, Plenum Press, New York.Google Scholar
  21. 16.
    Goebell, H., and Bode, C., 1971, Influence of ethanol and protein deficiency on the activity of alcohol dehydrogenase in the rat liver, in: Metabolic Changes Induced by Alcohol (G. A. Martini and C. Bode, eds.), pp. 23–31, Springer-Verlag, Berlin.CrossRefGoogle Scholar
  22. 17.
    Rachamin, G., MacDonald, J. A., Wahid, S., Clapp, J. L., Khanna, J. M., and Israel, Y., 1980, Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat, Biochem. J. 186: 483–490.PubMedGoogle Scholar
  23. 18.
    Meijer, A. J., Van Woerkom, T. C., Williamson, J. R., and Tager, J. M., 1975, Rate-limiting factors in the oxidation of ethanol by rat liver cells, Biochem. J. 150: 205–209.PubMedGoogle Scholar
  24. 19.
    Thurman, R. G., and Scholz, R., 1975, Effect of octanoate on ethanol metabolism, Fed. Proc. Fed. Am. Soc. Exp. Biol. 34: 634.Google Scholar
  25. 20.
    DeDuve, C., and Baudhuin, P., 1966, Peroxisomes (microbodies and related particles), Physiol. Rev. 46: 323–357.Google Scholar
  26. 21.
    Thurman, R. G., and Chance, B., 1969, Inhibition of catalase in perfused rat liver by sodium azide, Ann. N. Y. Acad. Sci. 168: 348–353.PubMedCrossRefGoogle Scholar
  27. 22.
    Sies, H., and Chance, B., 1970, The steady state level of catalase compound I in isolated hemoglobin-free perfused rat liver, FEBS Lett. 11: 172–176.PubMedCrossRefGoogle Scholar
  28. 23.
    Oshino, N., Chance, B., Sies, H., and Bücher, T., 1973, The role of H2O2 generation in perfused rat liver and the reaction of catalase compound I and hydrogen donors, Arch. Biochem. Biophys. 154: 117–131.PubMedCrossRefGoogle Scholar
  29. 24.
    Chance, B., and Oshino, N., 1971, Kinetics and mechanisms of catalase in peroxisomes of the mitochondrial fraction, Biochem. J. 122: 225–233.PubMedGoogle Scholar
  30. 25.
    Nichols, P., and Schonbaum, G. R., 1963, Catalases, in: The Enzymes, 2nd ed. (P. D. Boyer, H. A. Lardy, and K. Myrback, eds.), pp. 147–225, Academic Press, New York.Google Scholar
  31. 26.
    Shore, J. D., and Theorell, H., 1966, A kinetic study of ternary complexes in the mechanism of action of liver alcohol dehydrogenases, Arch. Biochem. Biophys. 116: 255–260.PubMedCrossRefGoogle Scholar
  32. 27.
    Orme-Johnson, W. H., and Ziegler, D. M., 1965, Alcohol mixed-function oxidase activity of mammalian liver microsomes, Biochem. Biophys. Res. Commun. 21: 78–84.PubMedCrossRefGoogle Scholar
  33. 28.
    Imai, Y., and Sato, R., 1967, Studies on the substrate interactions with P-450 in drug hy-droxylation by liver microsomes, J. Biochem. (Tokyo) 62: 239–249.Google Scholar
  34. 29.
    Lieber, C. S., and DeCarli, L. M., 1970, Hepatic microsomal ethanol-oxidizing system in vitro: Characteristics and adaptive properties in vivo, J. Biol. Chem. 245: 2505–2512.PubMedGoogle Scholar
  35. 30.
    Lieber, C. S., 1976, The metabolism of alcohol, Sci. Am. 234(3): 25–33.PubMedCrossRefGoogle Scholar
  36. 31.
    Koop, D. R., Morgan, E. T., Tarr, G. E., and Coon, M. J., 1982, Purification and characterization of a unique isoenzyme of cytochrome P-450 from liver microsomes of ethanol-treated rabbits, J. Biol. Chem. 257: 13, 951–13, 957.Google Scholar
  37. 32.
    Thurman, R. G., Ley, H. G., and Scholz, R., 1972, Hepatic microsomal ethanol oxidation: Hydrogen peroxide formation and the role of catalase, Eur. J. Biochem. 25: 420–430.PubMedCrossRefGoogle Scholar
  38. 33.
    Isselbacher, K. J., and Carter, E. A., 1970, Ethanol oxidation by liver microsomes: Evidence against a separate and distinct enzyme system, Biochem. Biophys. Res. Commun. 39: 530–537.PubMedCrossRefGoogle Scholar
  39. 34.
    Burnett, K. G., and Felder, M. R., 1980, Ethanol metabolism in Peromyscus genetically deficient in alcohol dehydrogenase, Biochem. Pharmacol. 29: 125–130.PubMedCrossRefGoogle Scholar
  40. 35.
    Hawkins, R., and Khanna, J. M., 1966, Effect of chronic intake of ethanol on rate of ethanol metabolism, Can. J. Physiol. Pharmacol. 44: 241–257.CrossRefGoogle Scholar
  41. 36.
    Mendelson, J., and Mello, N. K., 1966, Experimental analysis of drinking behavior of chronic alcoholics, Ann. N. Y. Acad. Sci. 133: 828–845.PubMedCrossRefGoogle Scholar
  42. 37.
    Videla, L., Bernstein, J., and Israel, Y., 1973, Metabolic alteration produced in the liver by chronic alcohol administration: Increased oxidative capacity, Biochem. J. 134: 507–514.PubMedGoogle Scholar
  43. 38.
    Thurman, R. G., McKenna, W. R., and McCaffrey, T. B., 1976, Pathways responsible for the adaptive increase in ethanol utilization following chronic treatment with ethanol: Inhibitor studies with the hemoglobin-free perfused rat liver, Mol. Pharmacol. 12: 156–166.PubMedGoogle Scholar
  44. 39.
    Thurman, R. G., and Scholz, R., 1977, Interactions of glycolysis and respiration in perfused rat liver: Changes in O2 uptake following addition of ethanol, Eur. J. Biochem. 75: 13–21.PubMedCrossRefGoogle Scholar
  45. 40.
    Iturriaga, H., Ugarte, G., and Israel, Y., 1980, Hepatic vein oxygenation, liver blood flow, and the rate of ethanol metabolism in recently abstinent alcoholic patients, Eur. J. Clin. Invest. 10: 211–218.PubMedCrossRefGoogle Scholar
  46. 41.
    Yuki, T., and Thurman, R. G., 1980, Swift increase in alcohol metabolism: Time course and involvement of glycolysis, Biochem. J. 186: 119.PubMedGoogle Scholar
  47. 42.
    Wendell, G. D., and Thurman, R. G., 1979, Effect of ethanol concentration on rates of ethanol elimination in normal and alcohol-treated rats in vivo, Biochem. Pharmacol. 28: 273–279.PubMedCrossRefGoogle Scholar
  48. 43.
    Bernstein, J., Videla, L., and Israel, Y., 1974, Hormonal influences in the development of the hypermetabolic state of the liver produced by chronic administration of ethanol, J. Pharmacol. Exp. Ther. 192: 583–591.Google Scholar
  49. 44.
    Sutherland, E. W., Oye, I., and Butcher, R. W., 1965, The action of epinephrine and the role of the adenyl cyclase system in hormone action, Recent Prog. Horm. Res. 21: 623–646.PubMedGoogle Scholar
  50. 45.
    Israel, Y., Videla, L., MacDonald, A., and Bernstein, J., 1973, Metabolic alterations produced in the liver by chronic alcohol administration. III. Comparison between the effects produced by ethanol and by thyroid hormones, Biochem. J. 134: 523–529.PubMedGoogle Scholar
  51. 46.
    Yuki, T., Thurman, R. G., Schwabe, U., and Scholz, R., 1980, Metabolic changes after prior treatment with ethanol: Evidence against an involvement of the Na+ + K+-activated ATPase in the increase in ethanol metabolism, Biochem. J. 186: 997–1000.PubMedGoogle Scholar
  52. 47.
    Rawat, A. K., and Lundquist, F., 1968, Influence of thyroxine on the metabolism of ethanol and glycerol in rat liver slices, Eur. J. Biochem. 5: 13–17.PubMedCrossRefGoogle Scholar
  53. 48.
    Fleckenstein, A., Kammermeier, H., Döring, H., and Freund, H. J., 1967, Zum Wirkungsmechanismus neuartiger Koronardiktatoren mit gleichzeitig Sauerstoff-einsparenden Myokard-effekten, Prenylomin und Prorenatid, Z. Kreislaufforsch 56: 716–744 and 839-835.PubMedGoogle Scholar
  54. 49.
    Peck, R. C., and Lefer, A. M., 1981, Protective effect of Nifedipine in the hypoxic perfused rat liver, Agents Actions 11: 421–424.PubMedCrossRefGoogle Scholar
  55. 50.
    Trump, F. G., and Arstila, A. U., 1975, Cell members and disease processes, in: Pathobiology of Cell Membranes (F. G. Trump and A. U. Arstila, eds.), pp. 1–103, Academic Press, New York.Google Scholar
  56. 51.
    Farber, J. L., and Young, E. E., 1981, Accelerated phospholipid degradation in anoxic rat hepatocytes, Arch. Biochem. Biophys. 211: 312–320.PubMedCrossRefGoogle Scholar
  57. 52.
    Jewell, S. A., Bellomo, G., Thor, H., Orrenius, S., and Smith, M. T., 1982, Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostatis, Science 207: 1257–1259.CrossRefGoogle Scholar
  58. 53.
    Poole-Wilson, P. A., Harding, D., Bourdillion, P., and Fleetwood, G., 1982, Mechanism of myocardial protection through Ca+ 2 blocade, in: Protection of Tissues against Hypoxia (A. Wauquier, ed.), pp. 351–364, Elsevier, Amsterdam.Google Scholar
  59. 53a.
    Lemasters, J. J., Stemkowski, C. J., Ji, S., and Thurman, R. G., 1983, Cell surface changes and enzyme release during hypoxia and reoxygenation in the isolated, perfused rat liver, J. Cell Biol. 97: 778–786.PubMedCrossRefGoogle Scholar
  60. 54.
    Krough, A., 1918, The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue, J. Physiol. (London) 52: 409–415.Google Scholar
  61. 55.
    Kessler, M., Höper, J., Lübbers, D. W., and Ji, S., 1981, Local factors affecting regulation of microflow, O2 uptake and energy metabolism, Adv. Physiol. Sci. 25: 155–162.Google Scholar
  62. 56.
    Kessler, M., Höper, J., and Kramel, B. A., 1976, Tissue perfusion and cellular function, Anaesthesiol 45: 186–199.CrossRefGoogle Scholar
  63. 57.
    Chance, B., Mayevsky, A., Goodwin, C., and Mela, L., 1974, Factors in oxygen delivery to tissue, Microvasc. Res. 8: 276–282.PubMedCrossRefGoogle Scholar
  64. 58.
    Chance, B., Cohen, P., Jöbsis, F., and Schoener, B., 1962, Intracellular oxidation-reduction states in vivo: The microfluorometry of pyridine nucleotide gives a continuous measurement of the oxidation state, Science 137: 1–10.Google Scholar
  65. 59.
    Chance, B., 1965, Reaction of oxygen with the respiratory chain in cells and tissues, Gen. Physiol. 49: 163–188.CrossRefGoogle Scholar
  66. 60.
    Chance, B., Barlow, C., Haselgrove, J., Nakase, Y., Quistorff, B., Matschinsky, F., and Mayevsky, A., 1978, Microheterogeneities of redox states of perfused and intact organs, in: Microenvironments and Metabolic Compartmentation (P. A. Srere and R. W. Estabrook, eds.), pp. 131–148, Academic Press, New York.Google Scholar
  67. 61.
    Matschinsky, F. M., Hintz, C. S., Reichlmeier, K., Quistorff, B., and Chance, B., 1978, The intralobular distribution of oxidized and reduced pyridine nucleotides in the liver of normal and diabetic rats, in: Microenvironments and Metabolic Compartmentation (P. A. Srere and R. W. Estabrook, eds.), pp. 149–166, Academic Press, New York.Google Scholar
  68. 62.
    Tamura, M., Oshino, N., Chance, B., and Silver, I., 1978, Optical measurements of intra-cellular oxygen concentration of rat heart in vivo, Arch. Biochem. Biophys. 191: 8–22.PubMedCrossRefGoogle Scholar
  69. 63.
    Oshino, N., Jamieson, D., and Chance, B., 1975, Optical measurements of the cata-lase-hydrogen peroxide intermediate (compound I) in the liver of anaesthetized rats and its implication to hydrogen peroxide production in situ, Biochem. J. 146: 53–65.PubMedGoogle Scholar
  70. 64.
    Sies, H., 1978, Cytochrome oxidase and urate oxidase as intracellular O2 indicators in studies of O2 gradients during hypoxia in liver, Adv. Exp. Med. Biol. 94: 561–566.Google Scholar
  71. 65.
    Jones, D. P., and Mason, H. S., 1978, Gradients of O2 concentration in hepatocytes, J. Biol. Chem. 253: 4874–4880.PubMedGoogle Scholar
  72. 66.
    Israel, Y., Kalant, H., Orrego, H., Khanna, J. M., Videla, L., and Phillips, J. M., 1975, Experimental alcohol-induced hepatic necrosis: Suppression by propylthiouracil, Proc. Natl. Acad. Sci. U.S.A. 72: 1137–1141.PubMedCrossRefGoogle Scholar
  73. 67.
    Ji, S., Lemasters, J. J., Christenson, V., and Thurman, R. G., 1982, Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: Evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia, Proc. Natl. Acad. Sci. U.S.A. 79: 5415–5419.PubMedCrossRefGoogle Scholar
  74. 68.
    Lemasters, J. J., Ji, S., and Thurman, R. G., 1981, Centrilobular injury following hypoxia in isolated, perfused rat liver, Science 213: 661–663.PubMedCrossRefGoogle Scholar
  75. 69.
    Belinsky, S. A., Popp, J. A., Kauffman, F. C., and Thurman, R. G., 1984, Trypan blue uptake as a new method to study zonal hepatotoxicity in the perfused liver, J. Pharmacol. Exp. Ther. 230: 755–760.PubMedGoogle Scholar
  76. 70.
    Israel, Y., Walfish, P. G., Orrego, H., Blake, J., and Kalant, H., 1979, Thyroid hormones in alcoholic liver disease, Gastroenterology 76: 116–122.PubMedGoogle Scholar
  77. 71.
    Hallé, P., Paré, P., and Kapstein, E., 1982, Double-blind, controlled trial of propylthiouracil in patients with severe acute alcoholic hepatitis, Gastroenterology 82: 925–931.PubMedGoogle Scholar
  78. 72.
    Szilagyi, A., Lerman, S., and Resnick, R. S., 1983, Ethanol, thyroid hormones and acute liver injury: Is there a relationship?, Hepatology 3: 593–600.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Ronald G. Thurman
    • 1
  • Sungchul Ji
    • 1
  • John J. Lemasters
    • 2
  1. 1.Department of PharmacologySchool of Medicine, University of North CarolinaChapel HillUSA
  2. 2.Department of AnatomySchool of Medicine, University of North CarolinaChapel HillUSA

Personalised recommendations