Gradients of O2 concentration in hepatocytes.

Jones, Dean P.; Mason, Howards S.

doi:10.1016/s0021-9258(17)34627-6

Cited by 185 publications

(10 citation statements)

References 46 publications

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“…Hypoxic regions have a greater reliance on anaerobic metabolism; as a consequence, the pH in these regions is lower than that generally found in adjacent well-oxygenated tissues . The H + concentration greatly influences the chemistry in these regions. − Because of the low oxygen tension, the rate of oxidation of NADH is decreased, resulting in an increase in the ratio of NADH/NAD + , as well as an increase in the redox potential of this couple . However, this effect is partially countered by the increase in H + concentration due to the impact of the H + ion concentration term in the equation below, which describes the redox potential of the NADH/NAD + couple: …”

Section: Resultsmentioning

confidence: 99%

Hypoxia-Selective Nitrobenzyloxycarbonyl Derivatives of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

et al. 1999

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Some 4- and 2-(nitrobenzyloxycarbonyl)-1, 2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines (4, 6, and 7) were synthesized and evaluated for their ability to exert preferential toxicity to hypoxic EMT6 mammary carcinoma cells using a colony-forming assay. Of these, the 4,5-dimethoxy-2-nitro analogue 6 (50 microM, 1-h exposure) caused greater than 3 logs of kill of hypoxic cells, with relatively minor toxicity to corresponding aerobic cells. The ability of 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues to reach and kill hypoxic cells of solid tumors was also demonstrated using intradermally implanted EMT6 solid tumors in mice. In addition, a possible source of toxicity to normal tissue, i. e., the activation of the 4-nitrobenzyl derivative 4 by glutathione S-transferase-catalyzed thiolysis, was essentially eliminated by replacing one of the benzylic methylene protons by a methyl group. The 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues also appear to be reduced more easily under acidic conditions (pH 6.0) than under neutral conditions, as measured by differential pulse polarography. Since the pH in hypoxic regions is often lower than that in adjacent aerobic regions, this property should aid in the cytotoxic action of these agents against hypoxic cells of solid tumors.

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Section: Resultsmentioning

confidence: 99%

Hypoxia-Selective Nitrobenzyloxycarbonyl Derivatives of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

et al. 1999

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“…One possibility is that 'downstream' regions of the liver lobule do not respond to glucagon because they are hypoxic. This alternative appears unlikely, however, since [02] was over 200 /M in 'downstream' areas, values far above the Km of cytochrome oxidase for oxygen (Jones & Mason, 1978). Moreover, adrenaline stimulated gluconeogenesis predominantly in 'downstream' regions , which could not occur if hepatocytes in 'downstream' regions were hypoxic.…”

Section: Effect Of Glucagon In the Starved Statementioning

confidence: 99%

Differential effect of glucagon on gluconeogenesis in periportal and pericentral regions of the liver lobule

Kinugasa¹,

Thurman²

1986

Biochemical Journal

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The effect of glucagon on gluconeogenesis was measured in periportal and pericentral regions of the liver lobule by monitoring changes in rates of O2 uptake on the surface of the perfused liver with miniature O2 electrodes after infusion of lactate. When lactate (2 mM) was infused into livers from starved rats perfused in the anterograde direction, O2 uptake was increased 2.5-fold more in periportal than in pericentral regions, reflecting increased energy demands for glucose synthesis. Under these conditions, glucagon infusion in the presence of lactate increased O2 uptake exclusively in periportal regions of the liver lobule. Thus, when perfusion is in the physiological anterograde direction, the metabolic actions of glucagon predominate in periportal regions of the liver lobule under gluconeogenic conditions in the starved state. When livers were perfused in the retrograde direction, however, glucagon stimulated O2 uptake exclusively in pericentral regions. Thus glucagon only stimulates gluconeogenesis in 'upstream' regions of the liver lobule irrespective of the direction of flow.

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“…3 At the plasma membrane there is a similar discontinuity in O 2 concentration between the internal milieu of the cell and the extracellular fluid surrounding it. 4 In order to understand the dynamics of respiration in a cell (or unicellular organism) during its changing functional states, the magnitude of these gradients and the consequent heterogeneity of O 2 concentration must be measured using a rapid, non-invasive 5 (or at best a minimally-invasive) method. 6 A variety of methods have been employed to measure O 2 concentrations in biological systems, 7 but those suitable for intracellular monitoring are rather few.…”

Section: Introductionmentioning

confidence: 99%

Probing intracellular oxygen by quenched phosphorescence lifetimes of nanoparticles containing polyacrylamide-embedded [Ru(dpp(SO3Na)2)3]Cl2

Coogan

Court

Gray

et al. 2010

Photochem Photobiol Sci

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Methods for measuring O(2) within living cells that rely on luminescent probes are hampered by several factors: local conditions of hydrophobicity, pH, ionic composition, dielectric constant, and photobleaching by free radical species. Use of a polymer-embedded luminophore should minimize these problems. Here we use a Ru(II) coordination complex embedded within 45 nm hydrodynamic diameter nanoparticles, and demonstrate that both phosphorescence intensity and lifetimes are O(2)-sensitive, both in aqueous suspensions and intracellularly (e.g. 4.06 versus 1.55 microseconds under anaerobic or aerobic conditions, respectively). Electroporation is necessary for incorporation of the nanoparticles into yeasts: it is more effective with the fission yeast, Schizosaccharomyces pombe, than for the budding yeast, Saccharomyces cerevisiae. However, electroporation was not required for particle uptake into a cultured human cell-line (mammary adenosarcoma MCF-7), although the intracellular distribution of the probe is more general to intracellular compartments when electroporation is employed. These procedures did not compromise vitality of cells over periods of 6 h, as judged by retention of structural characteristics evident in Nomarski interference or confocal microscopy images. Spatial resolution of intracellular structures defined by nanoparticle phosphorescence intensity imaging indicates potential usefulness of the application of lifetime imaging techniques for mapping of intracellular O(2) distributions.

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Gradients of O2 concentration in hepatocytes.

Cited by 185 publications

References 46 publications

Hypoxia-Selective Nitrobenzyloxycarbonyl Derivatives of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

Hypoxia-Selective Nitrobenzyloxycarbonyl Derivatives of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

Differential effect of glucagon on gluconeogenesis in periportal and pericentral regions of the liver lobule

Probing intracellular oxygen by quenched phosphorescence lifetimes of nanoparticles containing polyacrylamide-embedded [Ru(dpp(SO3Na)2)3]Cl2

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