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PubMed1970

Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart.

1. Transient and steady-state changes caused by acetate utilization were studied in perfused rat heart. The transient period occupied 6min and steady-state changes were followed in a further 6min of perfusion. 2. In control perfusions glucose oxidation accounted for 75% of oxygen utilization; the remaining 25% was assumed to represent oxidation of glyceride fatty acids. With acetate in the steady state, acetate oxidation accounted for 80% of oxygen utilization, which increased by 20%; glucose oxidation was almost totally suppressed. The rate of tricarboxylate-cycle turnover increased by 67% with acetate perfusion. The net yield of ATP in the steady state was not altered by acetate. 3. Acetate oxidation increased muscle concentrations of acetyl-CoA, citrate, isocitrate, 2-oxoglutarate, glutamate, alanine, AMP and glucose 6-phosphate, and lowered those of CoA and aspartate; the concentrations of pyruvate, ATP and ADP showed no detectable change. The times for maximum changes were 1min, acetyl-CoA, CoA, alanine and AMP; 6min, citrate, isocitrate, glutamate and aspartate; 2-4min, 2-oxoglutarate. Malate concentration fell in the first minute and rose to a value somewhat greater than in the control by 6min. There was a transient and rapid rise in glucose 6-phosphate concentration in the first minute superimposed on the slower rise over 6min. 4. Acetate perfusion decreased the output of lactate, the muscle concentration of lactate and the [lactate]/[pyruvate] ratio in perfusion medium and muscle in the first minute; these returned to control values by 6min. 5. During the first minute acetate decreased oxygen consumption and lowered the net yield of ATP by 30% without any significant change in muscle ATP or ADP concentrations. 6. The specific radioactivities of cycle metabolites were measured during and after a 1min pulse of [1-(14)C]acetate delivered in the first and twelfth minutes of acetate perfusion. A model based on the known flow rates and concentrations of cycle metabolites was analysed by computer simulation. The model, which assumed single pools of cycle metabolites, fitted the data well with the inclusion of an isotope-exchange reaction between isocitrate and 2-oxoglutarate+bicarbonate. The exchange was verified by perfusions with [(14)C]bicarbonate. There was no evidence for isotope exchange between citrate and acetyl-CoA or between 2-oxoglutarate and malate. There was rapid isotope equilibration between 2-oxoglutarate and glutamate, but relatively poor isotope equilibration between malate and aspartate. 7. It is concluded that the citrate synthase reaction is displaced from equilibrium in rat heart, that isocitrate dehydrogenase and aconitate hydratase may approximate to equilibrium, that alanine aminotransferase is close to equilibrium, but that aspartate transamination is slow for reasons that have yet to be investigated. 8. The slow rise in citrate concentration as compared with the rapid rise in that of acetyl-CoA is attributed to the slow generation of oxaloacetate by aspartate aminotransferase. 9. It is proposed that the tricarboxylate cycle may operate as two spans: acetyl-CoA-->2-oxoglutarate, controlled by citrate synthase, and 2-oxoglutarate-->oxaloacetate, controlled by 2-oxoglutarate dehydrogenase; a scheme for cycle control during acetate oxidation is outlined. The initiating factors are considered to be changes in acetyl-CoA, CoA and AMP concentrations brought about by acetyl-CoA synthetase. 10. Evidence is presented for a transient inhibition of phosphofructokinase during the first minute of acetate perfusion that was not due to a rise in whole-tissue citrate concentration. The probable importance of metabolite compartmentation is stressed.

Acetates↗
PubMed2001

Regulation of oxygen consumption at the onset of exercise.

Increased aerobic production of ATP at the onset of exercise could be limited by availability of metabolic substrates independent of O2, or interaction between O2 and metabolic substrates. We point out the importance of feedback control to match O2 supply to demand and discuss metabolic control at the onset of exercise.

Adenosine Triphosphate↗
PubMed1997

Some correlations between light transmission changes and some commonly used in vitro assays for the assessment of platelet concentrates.

This study aims to relate the duration of light transmission changes (LTCs) through platelet concentrates (PCs) to the results of a panel analytical procedures, many of which have correlated with platelet in vivo viability. LTCs of 16 PCs stored in P1-732 containers were studied over 10 d. On d 1, platelet counts and total PC ATP content were determined. On d 7, determination of the following parameters was carried out: pH, bicarbonate, the rate of oxygen consumption, the dispersion of the size distribution, the total platelet ATP content, the extent of shape change (ESC), the osmotic reversal reaction and extracellular lactate dehydrogenase (LDH) level. In addition, the rate of lactate production was determined over storage. A second series consisting of 18 PCs stored in P1-146 containers was monitored over 7 d. Mean platelet volume (MPV) was determined on d 3 and 7 and ESC was analysed on d 3. LTCs correlated significantly with pH, bicarbonate, the rate of oxygen consumption, increased platelet size distribution and decreased ESC. In addition, significant correlations were found when comparing LTCs with MPV(s). This study demonstrates that LTCs are closely related to parameters reflecting platelet metabolism.

Biological Assay↗
PubMedDate not supplied

Role of O2 in regulation of lactate dynamics during hypoxia: mathematical model and analysis.

The mechanistic basis of the relationship between O2 and lactate concentration in muscle is not fully understood. Although hypoxia can cause lactate (LA) accumulation, it is possible for LA accumulation to occur without hypoxia. Nevertheless, during conditions of low O2 availability, blood and tissue LA accumulation are used as indicators of hypoxia. To provide a framework for analyzing changes in energy metabolism and its regulation, we developed a mathematical model of human bioenergetics that links cellular metabolic processes to whole-body responses. Our model is based on dynamic mass balances and mechanistic kinetics in muscle, splanchnic and other body tissues for many substrates (glycogen, glucose, pyruvate, LA, O2, CO2, etc.) and control metabolites (e.g., ATP) through coupled reaction processes. Normal substrate concentrations in blood and tissues as well as model parameters are obtained directly or estimated indirectly from physiological observation in the literature. The model equations are solved numerically to simulate substrate concentration changes in tissues in response to disturbances. One key objective is to examine and quantify the mechanisms that control LA accumulation when O2 availability to the muscle is lowered. Another objective is to quantify the contribution of different tissues to an observed increase in blood lactate concentration. Simulations of system responses to respiratory hypoxia were examined and compared to physiological observations. Model simulations show patterns of change for substrates and control metabolites that behave similarly to those found experimentally. From the simulations, it is evident that a large decrease can occur in muscle O2 concentration, without affecting muscle respiration (Um,O2) significantly. However, a small decrease in Um,O2 (1%-2%) can result in a large increase in LA production (50%-100%). The cellular rate of oxygen consumption, Um,O2, which is coupled to ATP formation and NADH oxidation, can regulate other processes (e.g., glycolysis, pyruvate reduction) with high sensitivity through its effects on ADP/ATP and NADH/NAD. Thus, although LA metabolism does not depend directly on O2 concentration, it is indirectly affected by Um,O2, through changes in ADP/ATP, and NADH/NAD. Arterial LA concentration (Ca,LA) follows the pattern of change of muscle LA concentration (Cm,LA). Nevertheless, changes in Ca,LA, due to Cm,LA, are unlikely to be detected experimentally because changes in Cm,LA are small relative to the total LA concentrations in other tissues.

Adenosine Triphosphate↗
PubMed1986

31P NMR measurement of ATP synthesis rate in perfused intact rat hearts.

Using 31P NMR and the saturation-transfer method, the unidirectional rate of ATP synthesis was measured in isolated, Langendorff-perfused, isovolumic rat hearts operating at a rate pressure product of 25.6 +/- 2.5 (SE) X 10(3) mmHg X min-1 and consuming O2 at a rate of 35 +/- 2 mumol O2 X min-1 X (g dry wt)-1, at 37 degrees C. This rate was 7.2 +/- 0.9 mumol X s-1 X (g dry wt)-1 and was related to the rate of oxygen atom consumption by a ratio of 6.3 +/- 0.9. These data show that in the intact heart the unidirectional rate of ATP synthesis exceeds the net rate of ATP synthesis and consumption by approximately a factor of 2.

Adenosine Triphosphate↗
PubMed1998

Model of beta-cell mitochondrial calcium handling and electrical activity. II. Mitochondrial variables.

In the preceding article [Am. J. Physiol. 274 (Cell Physiol. 43): C1158-C1173, 1998], we describe the development of a kinetic model for the interaction of mitochondrial Ca2+ handling and electrical activity in the pancreatic beta-cell. Here we describe further results of those simulations, focusing on mitochondrial variables, the rate of respiration, and fluxes of metabolic intermediates as a function of D-glucose concentration. Our simulations predict relatively smooth increases of O2 consumption, adenine nucleotide transport, oxidative phosphorylation, and ATP production by the tricarboxylic acid cycle as D-glucose concentrations are increased from basal to 20 mM. On the other hand, we find that the active fraction of pyruvate dehydrogenase saturates, due to increases in matrix Ca2+, near the onset of bursting electrical activity and that the NADH/NAD+ ratio in the mitochondria increases by roughly an order of magnitude as glucose concentrations are increased. The mitochondrial ATP/ADP ratio increases by factor of < 2 between the D-glucose threshold for bursting and continuous spiking. According to our simulations, relatively small changes in mitochondrial membrane potential (approximately 1 mV) caused by uptake of Ca2+ are sufficient to alter the cytoplasmic ATP/ADP ratio and influence ATP-sensitive K+ channels in the plasma membrane. In the simulations, these cyclic changes in the mitochondrial membrane potential are due to synchronization of futile cycle of Ca2+ from the cytoplasm through mitochondria via Ca2+ uniporters and Na+/Ca2+ exchange. Our simulations predict steady mitochondrial Ca2+ concentrations on the order of 0.1 microM at low glucose concentrations that become oscillatory with an amplitude on the order of 0.5 microM during bursting. Abrupt increases in mitochondrial Ca2+ concentration > 5 microM may occur during continuous electrical activity.

Adenosine Triphosphate↗
PubMed2006

Oxygen consumption and metabolite concentrations during transitions between different work intensities in heart.

Steady-state metabolite (ADP, ATP, P(i), PCr, and NADH) concentrations usually differ little between different workloads with significantly different oxygen consumption rates in the heart. However, during transitions between steady states, metabolite concentrations may in some cases change transiently, exhibiting a significant overshoot or undershoot, whereas in other cases they approach near-exponentially new steady-state values. Oxygen consumption rate usually reaches the new steady-state value very quickly (within a few seconds). The present in silico studies, performed using a previously developed computer model of oxidative phosphorylation in the heart, demonstrate that such a behavior of the oxidative phosphorylation system can be reproduced only under the assumption that ATP usage, substrate dehydrogenation, and (particular steps of) oxidative phosphorylation are directly activated to a similar extend by some cytosolic factor/mechanism during transition from low work to high work (the so-called parallel-activation mechanism). Computer simulations show that some differences observed between different experimental systems can be explained by a slightly different balance of the activation of particular components of the system and/or by a delay in time of the activation/inactivation of substrate dehydrogenation and oxidative phosphorylation during low-to-high and high-to-low work transitions. Thus the presented theoretical approach offers a general idea that is able to unify, at least semiquantitatively, different experimental data available in the literature.

Adenosine Triphosphate↗
PubMed1996

Changes in the ability of ATP synthesis in the mitochondrial membrane in the rat liver injured by carbon tetrachloride.

We investigated the changes in the ability of adenosine triphosphate (ATP) synthesis in the inner mitochondrial membrane with the acute and chronic liver injuries by carbon tetrachloride (CCl4) in rats. The ability of ATP synthesis was evaluated by measuring the activity of proton ATPase and the ability of oxygen consumption using isolated mitochondria. In the acute liver injury, the ability of ATP synthesis at 6 hr after injection was preserved relatively well in spite of hepatocyte injuries. On the other hand, at 12 hr after CCl4 injection, the necrosis of hepatocyte was widely recognized. In the chronic liver injury, severe fibrosis was induced but the ability of ATP synthesis was kept as well as that in the normal liver. These results suggest that the mitochondria have some resistivity against radicals produced by CCl4.

Adenosine Triphosphate↗
PubMed1982

Mitochondrial respiratory control. Evidence against the regulation of respiration by extramitochondrial phosphorylation potentials or by [ATP]/[ADP] ratios.

To explore how mitochondria can respire at high physiological, extramitochondrial phosphorylation potentials, two series of experiments were conducted. In the first, intact rat liver mitochondria were incubated in oxygraph medium containing 5 mM succinate (+rotenone), 1.0 mM ATP, 20 mM glucose, pH 7.2, at 37 degrees C. Yeast hexokinase (0.02 to 1.0 IU) was added to establish steady state rates of respiration. Samples were removed, assayed for ATP, ADP, and Pi content, and ratios were calculated. As previously reported, low rates of respiration were observed at high phosphorylation potential ([ATP]/[ADP] x [Pi]) or [ATP]/[ADP] ratio values, and the rates of respiration increased as these values declined. In a second series of experiments, only sufficient hexokinase was added to potentially stimulate respiration to 90% of the ADP State 3 rate. At constant hexokinase, 0.35 IU, ATP (5 microM to 10.0 mM) was titrated into the medium to establish steady state rates of oxygen consumption. Under these conditions, low rates of respiration correlated with low [ATP]/[ADP] ratios and extramitochondrial phosphorylation potentials, while maximum rates of respiration were observed at high values of these ratios, the opposite of the previous experimental case. Therefore, it may be concluded that these extramitochondrial parameters per se exert little or no regulatory influence on the rates of respiration, and thus matrix ATP synthesis. In both cases, the concentrations of ADP correlated with respiratory rates. Double reciprocal plots were used to estimate the apparent KmADP for respiratory stimulation. The values are 56 microM for constant [ATP] and 15 microM at constant hexokinase. The value calculated from direct ADP pulses was 25 microM. Together, these results suggest that the most plausible explanation of respiratory control is the availability of ADP and the kinetics of its transport by the adenine nucleotide translocase, a hypothesis first proposed by Chance and Williams more than 25 years ago (Chance, B., and Williams, G. R. (1955) J. Biol. Chem. 217, 385-393).

Adenosine Diphosphate↗
PubMed1996

Effect of polyunsaturated fatty acids deficiency on oxidative phosphorylation in rat liver mitochondria.

Liver mitochondria isolated from controls or polyunsaturated fatty acid (PUFA) deficient rats were studied for oxidative phosphorylation. A PUFA-deficient diet led to a dramatic change in the fatty acid composition of mitochondrial lipid content, similar to that reported in the literature. Besides the changes in lipid composition, mitochondrial volume was enlarged (+45% in state 4 and two-fold in state 3). State 4 respiration was increased together with a decrease in protonmotive force. The non-ohmicity of the relationship between non-phosphorylating respiration and protonmotive force was more pronounced in the PUFA-deficient group. State 3 oxygen consumption as well as the rate of ATP synthesis showed no difference between the two groups, whereas the protonmotive force decreased substantially in mitochondria from PUFA-deficient animals. In contrast, ATP/O ratios were decreased in the PUFA-deficient group when determined at subsaturating ADP concentration. Taken together, these results are in agreement with both an increased non-ohmic proton leak and an increased redox slipping. The relative importance of these two effects on the overall efficiency of oxidative phosphorylation depends on both the rate of oxidative phosphorylation and the maintained protonmotive force. Hence, in isolated mitochondria the respective role of each effect may vary between state 4 and state 3.

Adenosine Triphosphate↗
PubMed1993

Hepatic mitochondrial energy production in rats with chronic iron overload.

BACKGROUND: Iron overload results in impaired hepatic mitochondrial oxidative metabolism. The current experiments evaluated the effects of iron overload on enzyme activities in the mitochondrial electron transport chain, on hepatic adenine nucleotide levels, and on hepatocellular oxygen consumption. METHODS: Hepatic iron overload was produced in rats using dietary carbonyl iron. Hepatic adenine nucleotides were assessed after freeze-clamping, mitochondrial enzyme activities and oxygen consumption were measured in isolated mitochondria, and oxygen consumption in isolated hepatocytes was determined. RESULTS: At a mean hepatic iron concentration of 4630 micrograms/g, there were no changes in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase activity (complex I-III), but there was a 35% reduction in succinate-cytochrome c reductase activity (complex II-III), and a 70% decrease in cytochrome c oxidase activity (complex IV). With mild iron loading (2060 micrograms/g), there was a 28% decrease in hepatic adenosine 5'-triphosphate (ATP) levels with no change in adenosine 5'-diphosphate (ADP) or adenosine 5'-monophosphate (AMP) levels, whereas, at a higher hepatic iron concentration (3170 micrograms/g), there was a 40% reduction in ATP levels, a 22% decrease in ADP levels, with no change in AMP levels. There was a 48% reduction in oxygen consumption in isolated iron-loaded hepatocytes. CONCLUSIONS: Chronic iron overload decreases hepatic mitochondrial cytochrome c oxidase activity, hepatocellular oxygen consumption, and hepatic ATP levels.

Adenosine Diphosphate↗
PubMedDate not supplied

Time dependent partial loss of the effects of isoproterenol on function and energy metabolism of isolated rat hearts.

In isolated perfused rat hearts (medium: Krebs-Ringer solution containing about 15% bovine red cells) the following parameters were estimated: heart rate (F), left intraventricular peak pressure (P), dP/dt, oxygen consumption (VO2); myocardial tissue content of glycogen, ATP, ADP, AMP, cAMP, phosphocreatin (PC) and inorganic phosphate (Pi). Isoproterenol (ISO) was administered to the non circulating system in the concentration range of 5 x 10(-10) to 5 x 10(-5) M for 4 min and 1 hour respectively by infusion into the perfusate close to the aortic canula. After administration period of 4 min dependent on the concentration of ISO, P, dP/dt, VO2 and the content of cAMP are increased. The ratios of PC/Pi and ATP/ADP as well as glycogen content are reduced. For an administration period of 1 hour at a level of 5 x 10(-9) M the effects of isoproterenol are maintained. At ISO concentration higher than 5 x 10(-9) M the effects on mechanical parameters and VO2 fall to the level of those values which are produced at 5 x 10(-9) M ISO. In contrast, high energy phosphates and glycogen content remain reduced while that of cAMP is elevated.

Adenine Nucleotides↗
PubMed2000

Preservation of mitochondrial function by diazoxide during sustained ischaemia in the rat heart.

1. A possible mechanism for the action of the K(ATP) channel opener diazoxide on the improvement of energy metabolism of ischaemic/reperfused hearts was examined. 2. Isolated, perfused rat hearts were subjected to 40 min ischaemia followed by 60 min reperfusion. Diazoxide at concentrations of 3 to 30 microM was present in the perfusion buffer for the last 15 min of pre-ischaemia. 3. Treatment of the perfused heart with diazoxide enhanced the post-ischaemic recovery of rate-pressure product, attenuated the post-ischaemic rise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and purine nucleosides and bases from the reperfused heart. Treatment of the heart with diazoxide also restored myocardial ATP and creatine phosphate and attenuated the decrease in mitochondrial oxygen consumption rate after reperfusion. This attenuation was maintained at the end of ischaemia as well as at the end of reperfusion. 4. In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of diazoxide, and then the mitochondrial oxygen consumption rate was determined. Hypoxia induced a decrease in the mitochondrial oxygen consumption rate of the skinned bundles to approximately 40% of the pre-hypoxic value. In contrast, treatment of the bundles with 30 microM diazoxide preserved the normal mitochondrial oxygen consumption rate during hypoxia. This effect was abolished concentration-dependently by the combined treatment with either the K(ATP) channel blocker glibenclamide or 5-hydroxydecanoate. 5. These results suggest that diazoxide is capable of attenuating ischaemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischaemia.

Adenosine Triphosphate↗
PubMed2006

Metabolic control over the oxygen consumption flux in intact skeletal muscle: in silico studies.

It has been postulated previously that a direct activation of all oxidative phosphorylation complexes in parallel with the activation of ATP usage and substrate dehydrogenation (the so-called each-step activation) is the main mechanism responsible for adjusting the rate of ATP production by mitochondria to the current energy demand during rest-to-work transition in intact skeletal muscle in vivo. The present in silico study, using a computer model of oxidative phosphorylation developed previously, analyzes the impact of the each-step-activation mechanism on the distribution of control (defined within Metabolic Control Analysis) over the oxygen consumption flux among the components of the bioenergetic system in intact oxidative skeletal muscle at different energy demands. It is demonstrated that in the absence of each-step activation, the oxidative phosphorylation complexes take over from ATP usage most of the control over the respiration rate and oxidative ATP production at higher (but still physiological) energy demands. This leads to a saturation of oxidative phosphorylation, impossibility of a further acceleration of oxidative ATP synthesis, and dramatic drop in the phosphorylation potential. On the other hand, the each-step-activation mechanism allows maintenance of a high degree of the control exerted by ATP usage over the ATP turnover and oxygen consumption flux even at high energy demands and thus enables a potentially very large increase in ATP turnover. It is also shown that low oxygen concentration shifts the metabolic control from ATP usage to cytochrome oxidase and thus limits the oxidative ATP production.

Adenosine Triphosphate↗
PubMed2005

Mitochondrial hydrogen peroxide production alters oxygen consumption in an oxygen-concentration-dependent manner.

Metabolic responses of mammalian cells toward declining oxygen concentration are generally thought to occur when oxygen limits mitochondrial ATP production. However, at oxygen concentrations markedly above those limiting to mitochondria, several mammalian cell types display reduced rates of oxygen consumption without energy stress or compensatory increases in glycolytic ATP production. We used mammalian Jurkat T cells as a model system to identify mechanisms responsible for these changes in metabolic rate. Oxygen consumption was 31% greater at high oxygen (150-200 microM) compared to low oxygen (5-10 microM). Hydrogen peroxide was implicated in the response as catalase prevented the increase in oxygen consumption normally associated with high oxygen. Cell-derived hydrogen peroxide, predominately from the mitochondria, was elevated with high oxygen. Oxygen consumption related to intracellular calcium turnover was shown, through EDTA chelation and dantrolene antagonism of the ryanodine receptor, to account for 70% of the response. Oligomycin inhibition of oxygen consumption indicated that mitochondrial proton leak was also sensitive to changes in oxygen concentration. Our results point toward a mechanism in which changes in oxygen concentration influence the rate of hydrogen peroxide production by mitochondria, which, in turn, alters cellular ATP use associated with intracellular calcium turnover and energy wastage through mitochondrial proton leak.

Adenosine Triphosphate↗
PubMed2000

Cold preservation injury in rat liver: effect of liposomally-entrapped adenosine triphosphate.

BACKGROUND/AIMS: Energy charge and capacity for adenosine triphosphate (ATP) synthesis have been demonstrated to play a major role in the maintenance of organ function after liver preservation for transplantation. The aim of this study was to evaluate whether a supply of liposomally-entrapped ATP during preservation could improve the energy state and metabolism of cold-stored rat liver. METHODS: In the first set of experiments, the uptake of ATP-containing liposomes and their effects on hepatic viability were determined in isolated perfused unstored rat liver. In the second set of experiments, rat livers were preserved for 18 h at 4 degrees C in UW solution in the presence of these liposomes, and effects on energy state, cell volume and metabolism were evaluated. In each part, data were compared with adequate control, unloaded liposome-treated, and free ATP-treated groups (n=6 in each group). RESULTS: In non-stored livers, ATP-containing liposomes were taken up by the liver; they did not alter hepatic viability and induced a decrease in energy substrate consumption (glucose and amino acids), and an improvement in intrahepatic ATP content (+23% vs. Control). Addition of liposomally-entrapped ATP during cold storage produced a significant attenuation of the decrease in hepatic ATP content (Lip ATP 2: 524+/-45 vs. Control 2: 364+/-106 nmol/g; p<0.05), and induced, during reperfusion, a decrease in proteolysis associated with an increase in cell volume compared with the other groups (Lip ATP 2: 633+/-63 vs. Control 2: 532+/-38, Unloaded Lip 2: 483+/-55 and Free ATP 2: 500+/-29 microl/g; p<0.01). CONCLUSIONS: These data indicate that liposomally-entrapped ATP represents an effective means to improve liver graft energy state and function. The decrease in protein degradation may be related to the modification of cell volume.

Adenosine Triphosphate↗
PubMed1998

Influence of glycine on the damage induced in isolated perfused rat liver by five hepatotoxic agents.

Livers of fasted rats were perfused over 120 min in a recirculating hemoglobin-free system. Hepatotoxic injury induced by the addition of 1-butanol (130.2 mmol/l), CdCl2 (0.1 mmol/l), CuCl2 (0.03 mmol/l), Na3VO4 (2 mmol/l) or t-butylhydroperoxide (t-BuOOH, 0.5 mmol/l) to the perfusate was shown by strong increases in lactate dehydrogenase (LDH) and glutamate-pyruvate transaminase (GPT) release, decreased oxygen consumption between 50 and 60%, and a nearly complete suppression of bile flow. Hepatic adenosine triphosphate (ATP) and reduced glutathione (GSH) concentrations were reduced by between 30 and 80%, and 20 and 80% respectively. Only Na3VO4 and t-BuOOH evoked increased releases of glutamate dehydrogenase (GLDH) in the perfusate. Malondialdehyde (MDA) concentrations were enhanced by all toxicants in the perfusate and by all except 1-butanol in the liver. The MDA increase, however, was much higher after Na3VO4 and t-BuOOH than after the other toxicants. When glycine (12 mmol/l) was added 30 min before the toxicants to the perfusate it prevented the enzyme releases induced by all hepatotoxic agents by about 80%. Furthermore, glycine prevented the Na3VO4 induced increase of MDA in liver and perfusate, the hepatic ATP and GSH level reductions induced by 1-butanol and attenuated the reduction of oxygen consumption induced by CuCl2 and t-BuOOH. Glycine, however, did not reverse the reductions of oxygen consumption induced by CdCl2 and Na3VO4, the suppressions of bile flow and, with the exception of 1-butanol, the decreases of hepatic ATP levels induced by all agents.

1-Butanol↗
PubMed1992

Disruption of mitochondrial function by suramin measured by rhodamine 123 retention and oxygen consumption in intact DU145 prostate carcinoma cells.

Suramin, an antiparasitic drug, has shown antitumor activity in humans. This may occur in part through disruption of energy balance, which is believed to be part of its antiparasitic action. Suramin disrupts mitochondrial function in intact DU145 prostate carcinoma cell monolayers as seen by its causing the release of rhodamine 123 from prestained cells beginning at about 10 microM in 96-well microtiter plates measured with a fluorescent plate scanner. This effect was similar to the ionophore carbonyl cyanide m-chlorophenylhydrazone, dissolved in ethanol at 0.01 N and indicates that suramin acts as a respiratory poison or an ionophore. This effect was confirmed by studies of oxygen consumption with a Clark oxygen electrode and cellular ATP content which demonstrated uncoupling of oxidative phosphorylation by 100 microM suramin, a clinically achievable plasma drug level.

Adenosine Triphosphate↗