Advertisement

Metabolic and Pathological Aspects of Hypoxia in Liver Cells

  • H. de Groot
  • A. Littauer
  • T. Noll

Abstract

The liver parenchymal cell, subsequently referred to as the liver cell, is among those mammalian cells which are dependent in their functions upon molecular oxygen. Hypoxia, i.e., O2 deficiency, is present when there are deviations in the functions of the liver cell from their normal values owing to a subnormal oxygen partial pressure (PO2). Among the oxidases and oxygenases of the liver cell, a unique role is played by cytochrome oxidase of the mitochondrial respiratory chain. The energy status and the oxidation-reduction status of the liver cell, and ultimately its viability, depend on its proper functioning. While cytochrome oxidase is characterized by an extraordinarily high affinity for O2, other oxidases and also the oxygenases of the liver cell usually possess a significantly lower affinity for O2. For this reason an impairment of the cytochrome oxidase activity due to O2 deficiency, and hence cell death, only occurs under severe hypoxia. However, certain pathological cell functions may already be altered under mild hypoxia, where cytochrome oxidase activity remains unaffected. An example is the increased reductive activation of halogenated alkanes to free radicals, resulting in an increased hepatotoxicity of these compounds under hypoxia.

Keywords

Xanthine Oxidase Cytochrome Oxidase Pathological Aspect Urate Oxidase Cytochrome Oxidase Activity 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahr HJ, King LJ, Nastainczyk W, Ullrich V (1980) The mechanism of chloroform and carbon monoxide formation from carbon tetrachloride by microsomal cytochrome P-450. Biochem Pharmacol 29: 2855–2861PubMedCrossRefGoogle Scholar
  2. Allen DG, Orchard DG (1983) Intracellular calcium concentration during hypoxia and metabolic inhibition in mammalian ventricular muscle. J Physiol (Lond) 339:107– 122Google Scholar
  3. Anundi I, King J, Owen DA, Schneider H, Lemasters JJ, Thurman RG (1987) Fructose prevents hypoxic cell death in liver. Am J Physiol 253: G390–G369PubMedGoogle Scholar
  4. Aw TY, Jones DP (1982) Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentration. J Biol Chem 257: 8997–9004PubMedGoogle Scholar
  5. Boag JW (1969) Oxygen diffusion and oxygen depletion problems in radiobiology. In: Ebert M, Howard A (eds) Current topics in radiation research. North-Holland, Amsterdam, pp 141–193Google Scholar
  6. Brattin WJ, Glende EA, Recknagel RO (1985) Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med 1: 27–38PubMedCrossRefGoogle Scholar
  7. Cheeseman KH, Albano EF, Tomasi A, Slater TF (1985) Biochemical studies of the metabolic activation of halogenated alkanes. Environ Health Perspect 64: 85–101PubMedCrossRefGoogle Scholar
  8. Cheung JY, Thompson IG, Bonventre JV (1982) Effects of extracellular calcium removal and anoxia on isolated rat myocytes. Am J Physiol 243: C184–C190PubMedGoogle Scholar
  9. Cheung JY, Leaf A, Bonventre JV (1986) Mitochondrial function and intracellular calcium in anoxic cardiac myocytes. Am J Physiol 250: C18–C25PubMedGoogle Scholar
  10. Cobbold PH, Bourne PK, Cuthbertson KSR (1985) Evidence from aequorin for injury of metabolically inhibited myocytes independently of free Ca2+. In: Spieckermann PG, Piper HM (eds) Isolated adult cardiac myocytes. Steinkopff, Darmstadt, pp 155–158Google Scholar
  11. Das DK, Engelman RM, Rousou J A, Breyer RH, Otani H, Lemeshow S (1986) Role of membrane phospholipids in myocardial injury induced by ischemia and reperfusion. Am J Physiol 251: H71–H79PubMedGoogle Scholar
  12. de Groot H, Haas W (1980) Oxygen-independent damage of cytochrome P-450 by CCU14-metabolites in hepatic microsomes. FEBS Lett 115:153–256CrossRefGoogle Scholar
  13. de Groot H, Noll T (1983) Halothane hepatotoxicity: relation between metabolic activation, hypoxia, covalent binding, lipid peroxidation and liver cell damage. Hepatology 3: 601–606PubMedCrossRefGoogle Scholar
  14. de Groot H, Noll T (1984) The crucial role of hypoxia in halothane-induced lipid peroxidation. Biochem Biophys Res Commun 119: 139–143PubMedCrossRefGoogle Scholar
  15. de Groot H, Noll T (1985a) Halothane-induced lipid peroxidation and glucose-6-phosphatase inactivation in microsomes under hypoxic conditions. Anesthesiology 62: 44–48PubMedCrossRefGoogle Scholar
  16. de Groot H, Noll T (1985b) Haloalkane free radicals and lipid peroxidation under low steadystate oxygen partial pressures. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF (eds) Free radicals in liver injury. IRL, Oxford, pp 185–189Google Scholar
  17. de Groot H, Noll T (1986) The crucial role of low steady-state oxygen partial pressures in haloalkane free-radical-mediated lipid peroxidation. Possible implications in haloalkane liver injury. Biochem Pharmacol 35:15–19PubMedCrossRefGoogle Scholar
  18. de Groot H, Noll T (1987a) Oxygen gradients: the problem of hypoxia. Biochem Soc Trans 15: 363–365PubMedGoogle Scholar
  19. de Groot H, Noll T (1987b) The role of physiological oxygen partial pressures in lipid peroxidation. Theoretical considerations and experimental evidence. Chem Phys Lipids 44: 209–226PubMedCrossRefGoogle Scholar
  20. de Groot H, Noll T, Sies H (1985a) Oxygen dependence and subcellular partitioning of hepatic menadione-mediated oxygen uptake. Studies with isolated hepatocytes, mitochondria, and microsomes in an oxystat system. Arch Biochem Biophys 243: 556–562PubMedCrossRefGoogle Scholar
  21. de Groot H, Noll T, Tölle T (1985b) Loss of latent activity of liver microsomal membrane enzymes evoked by lipid peroxidation. Studies of nucleoside diphosphatase, glucose-6-phosphatase, and UDP glucuronyl transferase. Biochim Biophys Acta 815: 91–96PubMedCrossRefGoogle Scholar
  22. de Groot H, Noll T, Rymsa B (1986) Alterations of the microsomal glucose-6-phosphatase system evoked by ferrous iron- and haloalkane free-radical-mediated lipid peroxidation. Biochim Biophys Acta 881:350–355PubMedCrossRefGoogle Scholar
  23. Farber JL, Young EE (1981) Accelerated phospholipid degradation in anoxic rat hepatocytes. Arch Biochem Biophys 211: 312–320PubMedCrossRefGoogle Scholar
  24. Farber JL, Chien KR, Mittnacht S (1981) The pathogenesis of irreversible cell injury in ischemia. Am J Pathol 102: 271–281PubMedGoogle Scholar
  25. Fowler CJ, Callingham BA (1978) Substrate-selective activation of rat liver mitochondrial monoamine oxidase by oxygen. Biochem Pharmacol 27:1995–2000PubMedCrossRefGoogle Scholar
  26. Hochachka PW (1986) Defence strategies against hypoxia and hypothermia. Science 231: 234–241PubMedCrossRefGoogle Scholar
  27. Houslay MD, Tipton KF (1973) The reaction pathway of membrane-bound rat liver mitochondrial monoamine oxidase. Biochem J 135: 735–750PubMedGoogle Scholar
  28. Israel Y, Kalant H, Orrego H, Khauna JM, Videla L, Phillips JM (1975) Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil. Proc Natl Acad Sci USA 72: 1137–1141PubMedCrossRefGoogle Scholar
  29. Jennings RB, Ganote CE, Reimer K (1975) Ischemic tissue injury. Am J Pathol 81:179–198PubMedGoogle Scholar
  30. Ji S, Lemasters JJ, Christenson V, Thurman RG (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 USA 79: 5415–5419PubMedCrossRefGoogle Scholar
  31. Jones DP (1981) Hypoxia and drug metabolism. Biochem Pharmacol 30:1019–1023PubMedCrossRefGoogle Scholar
  32. Jones DP (1984) Effect of mitochondrial clustering on O2 supply in hepatocytes. Am J Physiol 247: C83–C89PubMedGoogle Scholar
  33. Jones DP, Kennedy FG (1982) Intracellular oxygen supply during hypoxia. Am J Physiol 243: C247–C253PubMedGoogle Scholar
  34. Jones DP, Mason HS (1978) Gradients of oxygen concentration in hepatocytes. J Biol Chem 253: 4874–4880PubMedGoogle Scholar
  35. Kehrer JP, Piper HM, Sies H (1987) Xanthine oxidase is not responsible for reoxygenation injury in isolated-perfused rat heart. Free Radic Res Comm 3: 69–78CrossRefGoogle Scholar
  36. Kessler M, Höper J, Harrison DK, Skolasinska K, Klövekorn WP, Sebening F, Volkholz HJ, Beier I, Kernbach C, Rettig V, Richter H (1984) Tissue oxygen supply under normal and pathological conditions. In: Lübbers DW, Acker H, Leniger-Follert E, Goldstick TK (eds) Oxygen transport to tissue-V. Plenum, New York, pp 69–80CrossRefGoogle Scholar
  37. Kloner RA, Ganote CE, Whalen DA Jr, Jennings RB (1974) Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 74: 399–422PubMedGoogle Scholar
  38. Krebs HA, Cornell NW, Lund P, Hems R (1974) Isolated liver cells as experimental material. In: Lundquist R, Tygstrup N (eds) Regulation of hepatic metabolism. Academic, New York, pp 726–750Google Scholar
  39. Lemasters JJ, Stemkowski CJ, Ji S, Thurman RG (1982) Liver structure and function in hypoxia. In: Wauquier A et al (eds) Protection of tissues against hypoxia. Elsevier, Amsterdam, pp 15–30Google Scholar
  40. Lemasters JJ, Stemkowski CJ, Ji S, Thurman RG (1983) Cell surface changes and enzyme release during hypoxia and reoxygenation in the isolated, perfused rat liver. J Cell Biol 97: 778–786PubMedCrossRefGoogle Scholar
  41. Lemasters JJ, DiGuiseppi J, Nieminen A-L, Herman B (1987) Blebbing, free Ca2+ and mitochondrial membrane potential preceding cell death in hepatocytes. Nature 325: 78–81PubMedCrossRefGoogle Scholar
  42. Littauer A, Hugo-Wissemann D, Noll T, de Groot H (1988) Molecular oxygen is essential for carbon tetrachloride-mediated loss of cell viability in isolated hepatocytes. Life Sci Adv (in press)Google Scholar
  43. Longmuir IS (1957) Respiration rate of rat liver cells at low oxygen concentrations. Biochem J 65: 378–382PubMedGoogle Scholar
  44. Mansuy D, Battioni P (1985) Particular ability of cytochrome P-450 to form reactive intermediates and metabolites. In: Siest G (ed) Drug metabolism, molecular approaches and pharmalogical implications. Pergamon, Oxford, pp 195–203Google Scholar
  45. McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312: 159–163PubMedCrossRefGoogle Scholar
  46. Moorhouse PC, Grootveld M, Halliwell B, Quinlan JG, Gutteridge JMC (1987) Allopurinol and oxypurinol are hydroxyl radical scavengers. FEBS Lett 213: 23–28PubMedCrossRefGoogle Scholar
  47. Nayler WG (1983) Calcium and cell death. Eur Heart J. 4: 33–41PubMedCrossRefGoogle Scholar
  48. Nicholls DG (1982) Bioenergetics. Academic, LondonGoogle Scholar
  49. Noguchi T, Fong K-L, Lai EK, Alexander SS, King MM, Olson L, Poyer JL, McCay PB (1982) Specificity of a phenobarbital-induced cytochrome P-450 for metabolism of carbon tetrachloride to the trichloromethyl radical. Biochem Pharmacol 31: 615–624PubMedCrossRefGoogle Scholar
  50. Noll T, de Groot H (1984) The critical steady-state hypoxic conditions in carbon tetrachloride-induced lipid peroxidation in rat liver microsomes. Biochim Biophys Acta 795: 356–362PubMedCrossRefGoogle Scholar
  51. Noll T, de Groot H, Wissemann P (1986) A computer-supported oxystat system maintaining steady-state oxygen partial pressures and simultaneously monitoring oxygen uptake in biological systems. Biochem J 236: 765–769PubMedGoogle Scholar
  52. Noll T, Hugo-Wissemann D, Littauer A, de Sagara RM, de Groot H (1987) The decisive oxygen partial pressure-levels in haloalkane-mediated liver cell injury. Free Radic Res Comm 3: 293–298CrossRefGoogle Scholar
  53. Okuno F, Orrego H, Israel Y (1983) Calcium requirement for anoxic liver cell injury. Res Commun Chem Pathol Pharmacol 39: 437–444PubMedGoogle Scholar
  54. Oshino N, Sugano T, Oshino R, Chance B (1974) Mitochondrial function under hypoxic conditions: the steady states of cytochrome a + a3 and their relation to mitochondrial energy states. Biochim Biophys Acta 368: 298–310PubMedCrossRefGoogle Scholar
  55. Parks DA, Granger DN (1983) Ischemia-induced vascular changes: role of xanthine oxidase and hydroxyl radicals. Am J Physiol 245: G285–G289PubMedGoogle Scholar
  56. Parks DA, Bulkley GB, Granger DN (1983) Role of oxygen-derived free radicals in digestive tract diseases. Surgery 94: 415–422PubMedGoogle Scholar
  57. Petrovich DR, Finkelstein S, Waring AJ, Farber JL (1984) Liver ischemia increases the molecular order of microsomal membranes by increasing the cholesterol-to-phospholipid ratio. J Biol Chem 259:13217–13223PubMedGoogle Scholar
  58. Poulson LL, Ziegler DM (1979) The liver microsomal FAD-containing monooxygenase. Spectral characterization and kinetic studies. J Biol Chem 254: 6449–6455Google Scholar
  59. Recknagel RO, Ghoshal AK (1966) Lipoperoxidation as a vector in carbon tetrachloride hepatotoxicity. Lab Invest 15:132–146PubMedGoogle Scholar
  60. Reynolds ES, Yee AG (1967) Liver parenchymal cell injury. V. Relationships between patterns of chloromethane-C14 incorporation into constituents of liver in vivo and cellular injury. Lab Invest 16: 591–603PubMedGoogle Scholar
  61. Reynolds ES, Moslen MT (1980) Free-radical damage in liver. In: Pryor WA (ed) Free radicals in biology, vol IV. Academic, New York, pp 49–94Google Scholar
  62. Romero FJ, Pallardo FV, Bolinches R, Saez GT, Noll T, de Groot H (1987) Dependence of hepatic gluconeogenesis on oxygen partial pressure. Inhibitory effects of halothane. J Appl Physiol 63:1776–1780PubMedGoogle Scholar
  63. Roy RS, McCord JM (1983) Superoxide and ischemia: conversion of xanthine dehydrogenase to xanthine oxidase. In: Greenwald RA, Cohen G (eds) Oxy radicals and their scavenger systems. Elsevier, Amsterdam, pp 145–153Google Scholar
  64. Shen ES, Garry VF, Anders MW (1982) Effect of hypoxia on carbon tetrachloride hepatotoxicity. Biochem Pharmacol 31: 3787–3793PubMedCrossRefGoogle Scholar
  65. Shlafer M, Kane PF, Wiggins VY, Kirsh MM (1982) Possible role for cytotoxic oxygen metabolites in the pathogenesis of cardiac ischemic injury. Circulation 66:185–192Google Scholar
  66. Sies H (1977) Oxygen gradients during hypoxic steady states in liver. Urate oxidase and cytochrome oxidase as intracellular O2 indicators. Biol Chem Hoppe Seyler 358:1021–1032CrossRefGoogle Scholar
  67. Slater TF (1966) Necrogenic action of carbon tetrachloride in the rat: a speculative mechanism based on activation. Nature 209: 36–40PubMedCrossRefGoogle Scholar
  68. Snowdowne KW, Freudenrich CC, Borle AB (1985) The effects of anoxia on cytosolic free calcium, calcium fluxes, and cellular ATP levels in cultured kidney cells. J Biol Chem 260: 11619–11626PubMedGoogle Scholar
  69. Stewart JR, Blackwell WH, Crute SL, Loughlin V, Hess ML, Greenfield LJ (1982) Prevention of myocardial ischemia/reperfusion injury with oxygen free-radical scavengers. Surg Forum 33: 317–320Google Scholar
  70. Strubelt O, Breining H (1980) Influence of hypoxia on the hepatotoxic effects of carbon tetrachloride, paracetamol, allyl alcohol, bromobenzene and thioacetamide. Toxicol Lett 6:109–113PubMedCrossRefGoogle Scholar
  71. Sugano T, Oshino N, Chance B (1974) Mitochondrial functions under hypoxic conditions. The steady states of cytochrome c reduction and of energy metabolism. Biochim Biophys Acta 146: 340–358Google Scholar
  72. Thurman RG, Ji J, Lemasters JJ (1986a) Lobular oxygen gradients: possible role in alcohol-induced hepatotoxicity. In: Thurman RG, Kauffman FC, Jungermann K (eds) Regulation of hepatic metabolism. Intra- and intercellular compartmentation. Plenum, New York, pp 293–320Google Scholar
  73. Thurman RG, Kauffman FC, Baron J (1986b) Biotransformation and zonal toxicity. In: Thurman RG, Kauffman FC, Jungermann K (eds) Regulation of hepatic metabolism. Intra- and intercellular compartmentation. Plenum, New York, pp 321–382Google Scholar
  74. Tischler ME, Hecht P, Williamson JR (1977) Determination of mitochondrial/cytosolic metabolite gradients in isolated rat liver cells by cell disruption. Arch Biochem Biophys 181: 278–292PubMedCrossRefGoogle Scholar
  75. Uehleke H, Hellmer KH, Tabarelli S (1973) Binding of 14C-carbon tetrachloride to microsomal protein in vitro and formation of CHCl3 by reduced liver microsomes. Xenobiotica 3:1–11PubMedCrossRefGoogle Scholar
  76. Ullrich V (1979) Cytochrome P-450 and biological hydroxylation reactions. Top Curr Chem 83: 67–104PubMedCrossRefGoogle Scholar
  77. Wilson DF, Owen CS, Erecinska M (1979) Quantitative dependence of mitochondrial oxidative phosphorylation on oxygen concentration: a mathematical model. Arch Biochem Biophys 195: 494–504PubMedCrossRefGoogle Scholar
  78. Wolf CR, Harrelson WG, Nastainczyk WM, Philpot RM, Kalyanaraman R, Mason RP (1980) Metabolism of carbon tetrachloride in hepatic microsomes and reconstituted monooxygenase systems and its relationship to lipid peroxidation. Mol Pharmacol 18: 553–558PubMedGoogle Scholar
  79. Zimmerman HJ (1978) Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. Appleton-Century-Crofts, New YorkGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • H. de Groot
    • 1
  • A. Littauer
    • 1
  • T. Noll
    • 1
  1. 1.Institut für Physiologische Chemie IUniversität DüsseldorfDüsseldorfGermany

Personalised recommendations