Oxygen dependence of cellular metabolism: The effect of O2 tension on gluconeogenesis and urea synthesis in isolated rat hepatocytes

The dependencies of gluconeogenesis and urea synthesis on oxygen concentration were measured in suspensions of isolated rat hepatocytes and compared with the O2 dependence of cellular energy supply (reduction of cytochrome c, respiratory rate, mitochondrial [NAD+]/[NADH], lactate production, and [ATP]/[ADP][Pi]). As the oxygen concentration was decreased, production of both glucose and urea declined; the changes were observable at 20 μM oxygen and below, with the apparent Km values for both processes of near 5 μM. The similar dependence of gluconeogenesis and urea synthesis on oxygen concentration indicates that the two pathways have equal access to the cellular ATP supply, i.e., there is no evidence that either pathway is preferentially turned off to spare ATP for the other. The cellular energy state had an oxygen dependence similar to that of glucose and urea synthesis. It is suggested that the behavior of gluconeogenesis and urea production is a reflection of homeostatic regulation of cellular metabolism which is designed to respond to changes in [ATP]/[ADP][Pi].

[1]  H. Rasmussen,et al.  The effect of oxygen tension on the growth and metabolism of WI‐38 cells , 1976, Journal of cellular physiology.

[2]  H. Degn,et al.  The effect of energization on the apparent Michaelis-Mentne constant for oxygen in mitochondrial respiration. , 1974, The Biochemical journal.

[3]  B Chance,et al.  Mitochondrial functions under hypoxic conditions. The steady states of cytochrome c reduction and of energy metabolism. , 1974, Biochimica et biophysica acta.

[4]  D. Friend,et al.  HIGH-YIELD PREPARATION OF ISOLATED RAT LIVER PARENCHYMAL CELLS , 1969, The Journal of cell biology.

[5]  H. Chang,et al.  Oxygen transport in heterogeneous tissue. , 1974, Journal of theoretical biology.

[6]  T. Aw,et al.  Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentration. , 1982, The Journal of biological chemistry.

[7]  B Chance,et al.  Mitochondrial function under hypoxic conditions: the steady states of cytochrome alpha+alpha3 and their relation to mitochondrial energy states. , 1974, Biochimica et biophysica acta.

[8]  F. Ballard.  Regulation of gluconeogenesis during exposure of young rats to hypoxic conditions. , 1971, The Biochemical journal.

[9]  I. Silver,et al.  The oxygen dependence of cellular energy metabolism. , 1979, Archives of biochemistry and biophysics.

[10]  D. Wilson,et al.  Quantitative dependence of mitochondrial oxidative phosphorylation on oxygen concentration: a mathematical model. , 1979, Archives of biochemistry and biophysics.

[11]  J. Theodore,et al.  Differences in oxygen‐dependent regulation of enzymes between tumor and normal cell systems in culture , 1981, Journal of cellular physiology.

[12]  J. Taylor,et al.  Dependence of gluconeogenesis, urea synthesis, and energy metabolism of hepatocytes on intracellular pH. , 1984, The Journal of biological chemistry.

[13]  M. Erecińska,et al.  Homeostatic regulation of cellular energy metabolism: experimental characterization in vivo and fit to a model. , 1978, The American journal of physiology.

[14]  W. G. Taylor,et al.  Modulation of epithelial cell proliferation in culture by dissolved oxygen , 1982, Journal of cellular physiology.

[15]  I. Silver,et al.  Effect of oxygen tension on cellular energetics. , 1977, The American journal of physiology.

[16]  David F Wilson.  Regulation of in Vivo Mitochondrial Oxidative Phosphorylation , 1982 .

[17]  B Chance,et al.  A sensitifve bacterial luminescence probe for O2 in biochemical systems. , 1972, Biochimica et biophysica acta.

[18]  Gradients of O2 concentration in hepatocytes. , 1978, The Journal of biological chemistry.

[19]  J. Vanderkooi,et al.  Oxygen diffusion in biological and artificial membranes determined by the fluorochrome pyrene , 1975, The Journal of general physiology.

[20]  H. Bergmeyer,et al.  Adenosine-5′-diphosphate and Adenosine-5′-monophosphate , 1974 .

[21]  D. P. Jones,et al.  Intracellular oxygen supply during hypoxia. , 1982, The American journal of physiology.

[22]  H. Krebs,et al.  Acceleration of gluconeogenesis from lactate by lysine (Short Communication). , 1973, The Biochemical journal.

[23]  H. Krebs,et al.  Untersuchungen uber die Harnstoffbildung im Tierkörper , 1932 .

[24]  M. Kessler,et al.  Homeostasis of oxygen supply in liver and kidney. , 1973, Advances in experimental medicine and biology.

[25]  I. Longmuir.  Respiration rate of rat-liver cells at low oxygen concentrations. , 1957, The Biochemical journal.

[26]  H. Degn,et al.  Measurement of steady-state values of respiration rate and oxidation levels of respiratory pigments at low oxygen tensions. A new technique. , 1971, Biochimica et biophysica acta.

[27]  D. P. Jones,et al.  Intracellular O2 gradients in cardiac myocytes. Lack of a role for myoglobin in facilitation of intracellular O2 diffusion. , 1982, Biochemical and Biophysical Research Communications - BBRC.

[28]  A. Holian,et al.  Control of mitochondrial respiration: a quantitative evaluation of the roles of cytochrome c and oxygen. , 1977, Archives of biochemistry and biophysics.