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PubMed1992

Citrate alters Ca channel gating and selectivity in rabbit ventricular myocytes.

Addition of 10 mM citrate at constant free extracellular Ca concentration [( Ca]o; 2 mM) reduced contraction in rabbit ventricular muscle and isolated myocytes. We have recently shown that extracellular citrate decreases contraction and Ca current (ICa) in cardiac muscle by a direct effect on Ca channels rather than by Ca buffering per se [D. M. Bers, L. V. Hryshko, S. M. Harrison, and D. Dawson. Am. J. Physiol. 260 (Cell Physiol. 29): C900-C909, 1991]. Citrate rapidly depressed peak ICa and shifted both the peak ICa and the apparent reversal potential (Erev) to more negative potentials. When the impermeant cations, tetraethylammonium or N-methylglucamine were used instead of intracellular Cs, the citrate-induced shift in Erev was reduced or eliminated but depression of ICa was still observed. Thus citrate appears to alter the selectivity (PCa/PCs) of the Ca channel and reduce ICa. We also studied the effects of citrate on Na current through the Ca channel, observed when the divalent cation concentration is submicromolar. This current, termed INS for nonspecific, also exhibited leftward shifts in peak INS and smaller changes in Erev in the presence of citrate. However, neither peak INS nor single-channel conductance were affected by citrate. Thus the reduced PCa/PCs is due primarily to alteration of Ca permeation rather than monovalent cation permeation. Activation and inactivation curves for both ICa and INS were shifted toward more negative potentials by citrate. The shifts in gating and peak current to more negative membrane potentials would be consistent with a surface charge effect. The much larger shift in Erev for ICa (than for INS) is consistent with a reduction in Ca selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Effects of fasting on citrate transport by the brush-border membrane of rat kidney.

Fasting in rats decreases plasma citrate levels and reduces urinary citrate excretion by the kidney. After 72 h of fasting, the endogenous renal citrate clearance was decreased and the fractional citrate excretion was 0.026 +/- 0.008 compared with 0.218 +/- 0.030 in control fed rats. To determine whether these findings result from an adaptation in citrate transport across the plasma membrane of the renal tubular cell, Na+ gradient-dependent [14C]citrate uptake was examined in brush-border membrane vesicles (BBMW) prepared from kidneys of fed and 72-h fasted rats. The initial rate (10 s) of Na+ gradient-stimulated uptake of 100 microM citrate was significantly increased in BBMW from kidneys of fasted rats (380 +/- 24.9 pmol/mg prot) compared with fed rats (255 +/- 24.9 pmol/mg prot). Arterial acid-base parameters from conscious animals were similar between the two groups. There was no significant difference in Na+-independent citrate uptake or in L-glutamine uptake measured at 20 s in BBMV from the kidneys of fasted compared with fed rats. An adaptation occurs in the brush-border membrane of the renal tubular cell of fasting rats, unrelated to systemic acidosis, that may result in increased reabsorption of citrate.

Acid-Base Equilibrium↗

PubMed1977

Citrate uptake and oxidation by fragments of rat ventral prostate.

Citrate oxidation was studied utilizing an in vitro preparation of rat ventral prostate which was very similar, with respect to citrate metabolish, to the intact prostate. The rate of citrate oxidation was very slow in comparison to kidney, although citrate entered prostatic tissue and accumulated intracellularly. Citrate was converted to isocitrate at a rate which resulted in a constant citrate/isocitrate ratio over a 10-fold variation in medium citrate concentration. The prostate oxidized significantly more alpha-ketoglutarate and malate than citrate. These results suggested that limited citrate oxidation could account for the accumulation of high prostatic citrate levels.

Animals↗

PubMed1978

Citrate and isocitrate utilization by rat ventral prostate mitochondria.

Isolated rat ventral prostate mitochondria preparations were capable of utilizing exogenous isocitrate with some resulting production of citrate. The prostate preparation did not utilize citrate or alphaKG. Citrate utilization via isocitrate seems to be limited by a unique aconitase activity which permits isocitrate to citrate but not citrate to isocitrate conversion. In contrast, kidney cortex mitochondria (under these same conditions) were capable of utilizing citrate, isocitrate, and alphaKG, and also converting isocitrate to citrate. The results support the view that citrate oxidation by prostate may be limited at the aconitase step, and thus may be a key step in accounting for the uniquely high citrate content of prostate.

Animals↗

PubMed2000

Role of citrate synthase in aldosterone-mediated sodium reabsorption.

Aldosterone and other mineralocorticoids increase citrate synthase activity in the kidney and enhance renal sodium reabsorption, but it is unclear whether the increased citrate synthase activity is involved in renal sodium transport. We used the Wistar-Furth rat, an inbred strain found to be deficient in renal citrate synthase activity, as an experimental model to investigate this issue. We confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth rats was decreased compared with that from control Wistar rats (by 28%). Similarly, urinary citrate excretion was 23% lower in Wistar-Furth rats. Subnormal citrate formation in Wistar-Furth rats could not be accounted for by differences in systemic pH or circulating potassium levels. Because renal citrate synthase activity was reduced in Wistar-Furth rats, we hypothesized that renal sodium excretory responses to mineralocorticoids would be reduced as well. Four-hour sodium excretion after intraperitoneal injection of 5 microg of aldosterone was reduced by 56% in adrenalectomized Wistar rats and by 52% in adrenalectomized Wistar-Furth rats (both P<0.01 compared with vehicle injection). Similarly, the pattern of urinary sodium excretion in response to subcutaneous injections of deoxycorticosterone acetate over a 2-week period was similar in adrenalectomized Wistar and Wistar-Furth rats. In summary, acute and chronic antinatriuretic responses to mineralocorticoids are maintained in Wistar-Furth rats at the level of Wistar rats, despite the marked reduction in citrate synthase activity. These findings are not consistent with an important role for citrate synthase activity in mineralocorticoid-mediated renal sodium transport.

Adrenalectomy↗

PubMed1975

Effect of volume expansion on renal citrate and ammonia metabolism in KCl-deficient rats.

When rats with desoxycorticosterone acetate (DOCA)-induced potassium chloride deficiency are given sodium chloride there is simultaneously a partial correction of metabolic alkalosis and a marked reduction in urinary citrate excretion and renal citrate content. To examine DOCA's role in this phenomenon and to determine how sodium chloride alters renal metabolism, rats were made KC1 deficient using furosemide and a KC1-deficient diet. Renal citrate and ammonia metabolism were then studied after chronic oral sodium chloride administration or acute volume expansion with isotonic mannitol. Although both maneuvers partially corrected metabolic alkalosis, sodium chloride raised serum chloride concentration while mannitol significantly decreased it. Urinary citrate excretion decreased to 10% of control in rats given NaCl and to 50% of control in rats infused with mannitol. The filtered load of citrate was constant or increased indicating increased tubular citrate reabsorption. Renal cortical citrate content also decreased approximately 50%. Renal cortical slices from KCl-deficient rats incubated in low or normal chloride media produced equal amounts of 14CO2 from (1, 5-14C) citrate. In addition, urinary ammonia excretion increased by over 300% in both groups. This occurred in the mannitol group despite increased urinary pH and flow rate indicating a rise in renal ammonia production. It seems that neither DOCA nor an increase in serum chloride concentration explains the experimental results. Rather, it appears that volume expansion is responsible for increased renal tubular citrate reabsorption and renal ammonia production. As these renal metabolic responses ordinarily occur in response to acidosis, the data are consistent with the hypothesis that volume expansion reduces renal cell pH in 3KCl-deficient rats.

Ammonia↗

PubMed2005

Commercial low-citrate anticoagulation haemofiltration in high risk patients with frequent filter clotting.

This study assessed the safety and efficacy of a commercial low-citrate concentration-based pre-filter replacement fluid during continuous veno-venous haemofiltration (CVVH) in patients with frequent filter clotting and high risk of bleeding. We used a commercial low-citrate fluid as pre-dilution replacement fluid during CVVH (citrate: 11 mmol/l (33 meq/l), sodium: 140 mmol/l, chloride: 108 mmol/l and potassium: 1 mmol/l). A calcium and magnesium infusion was delivered separately by central line for the maintenance of serum ionized calcium (Cai) and total magnesium (Mg). In this prospective observational study, 30 patients, 124 filters and 1,515 treatment-hours were observed. Median filter life of citrate CVVH was 9.5 hours. Filter life in the 48 hours prior to citrate CVVH was also observed. In the patients on prior non-anticoagulant CVVH (n=14) filter life increased significantly with citrate (9.5 hours vs 5 hours; P<0.0001). In patients on prior heparin CVVH (n = 15), filter life was similar with citrate (10 hours vs 8 hours; P = 0.68). However, in patients with prior early/frequent filter clotting despite heparin (n = 11) filter life increased significantly (10 hours vs 7 hours; P=0.038). Of 411 serum Cai measurements, none showed a Cai < 0.85 mmol/l and, of 84 observations, none showed a serum Mg<0. 6 mmol/l. One patient with sepsis and shock needed to cease citrate CVVH because of progressive ionized hypocalcaemia and increasing anion gap. No other adverse effects were observed. In selected patients, CVVH with a commercial low-citrate concentration solution as pre-filter replacement fluid and a simultaneous calcium and magnesium infusion protocol appears generally safe. Filter life was acceptable and superior to that achieved with previous treatment.

Acute Kidney Injury↗

PubMed2005

A comparison of two citrate anticoagulation regimens for continuous veno-venous hemofiltration.

AIMS: To assess the safety and efficacy of two different commercial citrate containing pre-filter replacement fluids during continuous veno-venous hemofiltration (CVVH) in patients with frequent filter clotting. SETTING: Four intensive care units. PATIENTS: Sixty-three critically ill patients with acute renal failure (ARF). DESIGN: Prospective observational study. METHODS: We used a commercial citrate fluid (citrate: 11 mmol/L -fluid A) as predilution replacement for CVVH. We then changed to a new commercial citrate fluid (citrate: 14 mmol/L-fluid B) as replacement fluid and performed statistical comparisons. Replacement fluid rate was fixed at 2,000 ml/hour. RESULTS: Filter life was 12.2 hour with fluid A compared with 17.1 hour with fluid B on average (p=0.0001). Mean post filter ionized calcium concentration was 0.52 mmol/L with fluid A compared with 0.40 mmol/L with fluid B (p<0.0001). Citrate intolerance led to cessation of treatment in one patient with fluid A and one patient with fluid B. Overall ionized calcium levels were higher (A: 1.18 vs B: 1.13 mmol/L; p<0.0001) and bicarbonate was lower (A: 22.4 vs B: 24.5 mmol/L; p<0.0001) during treatment with fluid A. Alkalemia was seen in 10 patients treated with fluid A and 16 patients treated with fluid B (NS). CONCLUSIONS: We have developed a simple approach to regional citrate anticoagulation for CVVH using a commercial citrate-containing fluid as replacement fluid. Increasing citrate concentration from 11 to 14 mmol/L increased filter life while maintaining relative safety and simplicity.

Acute Kidney Injury↗

PubMed1987

Enhanced calcium bioavailability from a solubilized form of calcium citrate.

An improved formulation of calcium citrate with higher aqueous solubility and bioavailability was sought. Mixtures of calcium hydroxide and citric acid, with a calcium to citrate molar ratio ranging from 0.67-1.5, dissolved rapidly in water, creating a metastably supersaturated solution. The presence of an excess of citrate in the mixture delayed the precipitation of calcium citrate and kept calcium in solution longer. Thus, the mixture with a calcium to citrate molar ratio of 1.25, containing 500 mg elemental calcium, dissolved in 300 mL water within 2 min and could be kept in solution for 1 h at a wide pH range between 2 and 7. Intestinal calcium absorption, measured from the increment in urinary calcium during the second 2 h following an oral calcium load (500 mg) in 15 normal subjects was significantly higher from the mixtures (calcium to citrate molar ratios of 1.5 and 1.25) than from tricalcium dicitrate. The fractional calcium absorption, obtained from fecal recovery of radiocalcium after oral administration of 500 mg calcium prelabeled with 47Ca in 11 normal subjects, was also higher for the mixture with a calcium to citrate molar ratio of 1.25. The most efficient calcium absorption was obtained with the mixture of calcium hydroxide and citric acid with a calcium to citrate molar ratio of 1.25. The increment in urinary calcium after an oral load with this mixture was 62.4% greater than that obtained with tricalcium dicitrate [0.138 +/- 0.056 (+/- SD) vs. 0.085 +/- 0.086 mg/dL glomerular filtrate; P less than 0.05]. The fractional calcium absorption was 88.4% higher (0.324 +/- 0.107 vs. 0.172 +/- 0.061; P less than 0.05). This mixture provided the highest concentration of ionic calcium, indicating that calcium (rather than calcium-citrate complex) is the fraction absorbed from the intestinal tract. This study, therefore, suggests that a liquid calcium preparation formulated from the mixture of calcium hydroxide and citric acid is more effective than a solid preparation of tricalcium dicitrate in providing soluble and bioavailable calcium.

Adult↗

PubMed2005

Effect of sildenafil citrate on the cardiovascular system.

Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6(O4)S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.

Adult↗

PubMed1998

Citrate promotes attachment of Prevotella nigrescens (intermedia) ATCC 25261 to hydroxyapatite.

Large quantities of Prevotella nigrescens (intermedia) ATCC 25261 (P. nigrescens) cells adhere to hydroxyapatite (HA) treated with citrate, but do not adhere experimental pellicle prepared from human whole saliva. To determine the nature of the citrate responsible for promoting P. nigrescens cell adhesion, the duration and frequency of citrate treatment of HA and the inhibitory effect of other carboxylates were tested. The citrate rapidly adhered to HA beads in less than 15 min. With a lower concentration (0.4 mM) of citrate, four treatments of HA were required to promote the maximum adherence to P. nigrescens cells. Citrate-enhanced P. nigrescens cell adherence to HA beads was also inhibited in the presence of cis-aconitate, oxaloacetate and oxalsuccinate. It was also found that P. nigrescens cells heated to 65 degrees C or higher for 5 min could no longer become attached to citrate-treated HA. These data suggest that citrate is one of the essential factors responsible for P. nigrescens cell attachment to apatitic surfaces, and that P. nigrescens' adhesion to citrate is extremely heat-sensitive.

Aconitic Acid↗

PubMed2000

Effects of dietary potassium citrate supplementation on urine pH and urinary relative supersaturation of calcium oxalate and struvite in healthy dogs.

OBJECTIVE: To assess the effect of dietary potassium citrate supplementation on the urinary pH, relative supersaturation of calcium oxalate and struvite (defined as the activity product/solubility product of the substance), and concentrations of magnesium, ammonium, phosphate, citrate, calcium, and oxalate in dogs. ANIMALS: 12 healthy adult dogs. PROCEDURE: Canned dog food was fed to dogs for 37 days. Dogs were randomly allocated to 3 groups and fed test diets for a period of 8 days. Study periods were separated by 6-day intervals. During each study period the dogs were fed either standard diet solus (control) or standard diet plus 1 of 2 types of potassium citrate supplements (150 mg potassium citrate/kg of body weight/d) twice daily. Urinary pH, volume and specific gravity, relative supersaturation of calcium oxalate and struvite, and concentrations of magnesium, ammonium, phosphate, calcium, oxalate, and citrate were assessed for each treatment. RESULTS: Mean urine pH was not significantly affected by dietary potassium citrate supplementation, although urine pH did increase by 0.2 pH units with supplementation. Diets containing potassium citrate maintained a higher urine pH for a longer part of the day than control diet. Three Miniature Schnauzers had a significantly lower urinary relative calcium oxalate supersaturation when fed a diet supplemented with potassium citrate, compared with control diet. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary potassium citrate supplementation has limited effects on urinary variables in most healthy dogs, although supplementation results in maintenance of a higher urine pH later in the day. Consequently, if supplementation is introduced, dogs should be fed twice daily and potassium citrate should be given with both meals or with the evening meal only.

Animals↗

PubMed1992

Ranitidine and sodium citrate as prophylaxis against acid aspiration syndrome in obstetric patients undergoing caesarean section.

The efficacy of a single oral dose of 0.3M of sodium citrate alone as a prophylaxis against acid aspiration syndrome in obstetric patients undergoing LSCS (elective and emergency) was compared with that of intravenous ranitidine. One group of patients was given 30 ml of 0.3M sodium citrate orally just before the induction of anaesthesia while the other group was given 50mg of ranitidine intravenously together with the 30ml of 0.3M sodium citrate. This was done for both the elective and the emergency groups of patients. There was no significant difference in the mean pH of the gastric aspirate obtained from those given sodium citrate alone and those given sodium citrate and ranitidine in either the elective or the emergency group. However, in the emergency group, those who were given sodium citrate alone tend to have a larger volume of gastric aspiration when compared with those given ranitidine together with the sodium citrate. There were significantly more patients with gastric aspirates of more than 25ml in the emergency group to which sodium citrate alone was given. It would appear that supplementing an intravenous dose of ranitidine with the oral dose of sodium citrate is useful in emergency LSCS as a prophylaxis against acid aspiration syndrome.

Adult↗

PubMed1990

Citrate haemodialysis.

We describe our experience with sodium citrate as anticoagulant in the haemodialysis of 15 patients who were at high risk for bleeding. Furthermore, in six of these patients who were on prolonged citrate dialysis, the last month of heparin dialysis was compared with the first month in which citrate was used as anticoagulant. Our series confirms the suitability of citrate as anticoagulant in patients who are at high risk for bleeding. In the prolonged citrate dialysis group, however, there were complaints of paraesthesias. Probably, the citrate-induced metabolic alkalosis and the relatively low serum calcium concentration observed in these patients contributed to these complaints. To limit these side effects the acetate concentration in the dialysate needs to be reduced and, as magnesium also complexes with citrate, a calcium- and magnesium-free dialysate should be used to reduce the citrate infusion rate and thus the alkaline load in these patients. Furthermore, lowering the calcium infusion rate in order to lower the citrate infusion rate is not indicated because this induces low serum calcium concentration.

Adult↗

PubMed1990

Solubilization and reconstitution of the Na(+)-dependent citrate carrier of Klebsiella pneumoniae.

The citrate carrier of Klebsiella pneumoniae fermenting this substrate has been solubilized from the bacterial membranes with Triton X-100. The transport function was reconstituted by incorporation of the carrier into proteoliposomes using a freeze-thaw sonication procedure. Citrate uptake into these proteoliposomes required the presence of Na+ ions on the outside; the amount of citrate accumulated increased as the external Na+ concentration increased from 0 to 100 mM. Proteoliposomes preloaded with citrate catalyzed citrate counterflow when added to external [14C] citrate. Sodium ions were required for counterflow activity. The kinetics of citrate uptake, counterflow, or efflux were not influenced by an inside negative membrane potential, and the presence of the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone was without effect on citrate uptake. The data therefore suggest an electroneutral Na(+)-citrate symport mechanism for the transport of this tricarboxylic acid into K. pneumoniae.

Biological Transport↗

PubMed1979

Citrate in daily and fasting urine: results of controls, patients with recurrent idiopathic calcium urolithiasis, and primary hyperparathyroidism.

In three groups--patients with recurrent calcium urolithiasis (RCU), patients with primary hyperparathyroidism (pHPT), and healthy controls--citrate was measured enzymatically in 24 and in 2-hr urine after an overnight fast. Citrate excretion per 24 hr was significantly lower in RCU than in age and sex matched controls, whereas there was no significant difference in citrate excretion in urines from the 2-hr morning collection. In pHPT citrate was also lower than in controls and fell within the range of RCU of comparable age. Both categories of urines (24 and 2hr) have in common the characteristic that the actual citrate concentration is lower by 50 per cent in RCU and pHPT than in controls, mainly as a result of the higher urine volume. Correction of citrate for creatinine does not disclose further differences among the populations studied but conversely hampers exact interpretation of urinary citrate in the absence of strict separation of individuals according to sex and age. From these data we conclude that (i) a low excretion and concentration of urinary citrate is detectable in calcium lithiasis and may contribute to a deficiency in inhibitory activity against nucleating processes in stone-forming urine; and (ii) the differences in urinary citrate elicited in samples of 24 and 2-hr morning urine are of unknown origin and merit further investigations.

Adult↗

PubMed1983

The induction of liver tumors by 239Pu citrate or 239PuO2 particles in the Chinese hamster.

The influence of radiation dose distribution on the frequency of 239Pu-induced liver tumors was evaluated in the Chinese hamster. Different concentrations of 239Pu citrate 239PuO2 particles of known sizes were injected intravenously via the jugular vein. About 60% of the injected 239Pu citrate was deposited in the liver and 40% in the bone. The 239Pu citrate was rather uniformly distributed throughout the liver parenchyma. Injected plutonium oxide particles were taken up by the reticuloendothelial system with 90% of the body burden deposited in the liver. The 239PuO2 particles were localized in the Kupffer cells and produced nonuniform dose distributions that were dependent on particle size. There was an activity- and dose-dependent increase in the incidence of total liver parenchymal cell tumors following injection with either plutonium particles or citrate. For animals that received 14.0-, 2.7-, 0.3-, and 0.04-Gy dose to liver from 239Pu citrate the cumulative tumor incidence was 39, 32, 5, and 0%, respectively. Animals that were injected with the 0.24 micron 239PuO2 particles had doses of 42.0, 7.2, and 0.8 Gy to the liver and tumor incidences of 34, 26, and 5%, respectively. Plutonium citrate also produced hemangiosarcomas of the liver and tumors in bone and bone marrow. The latent period for liver tumor appearance in animals exposed to 239Pu citrate or 239PuO2 particles increased as the injected activity decreased. For animals injected with a similar total activity (7.4 Bq/g), the lifetime cumulative liver tumor incidence was similar for animals exposed to either 239Pu citrate (32%) or 239PuO2 (26%). There was little effect of particle size on liver tumor incidence. These data indicate that, in Chinese hamster liver, local radiation dose distribution is less important in altering tumor incidence than injected activity or average dose. However, the more uniform irradiation from 239Pu citrate administration was more effective in cancer production than the nonuniform irradiation from 239PuO2 particles.

Alpha Particles↗

PubMed1984

Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol.

Mitochondria isolated from rapidly growing, poorly differentiated Morris hepatoma 3924A have been found to export the citrate they generate from pyruvate, at a rate greater than four times that of control liver preparations. These 3924A mitochondria fail to exhibit state 3 respiration when either pyruvate or citrate are supplied as respiratory fuels. Nevertheless, substrates that join the Krebs cycle beyond citrate (viz. isocitrate, glutamate, alpha-ketoglutarate, and succinate) are readily oxidized by tumor 3924A mitochondria. Blocking the tricarboxylate anion exchange carrier with the citrate transport inhibitor 1,2,3-benzenetricarboxylate restores the ability of tumor 3924A mitochondria to respire with pyruvate or citrate. Slowly growing, minimally deviated Morris hepatoma 16 possesses mitochondria that do not display discernably altered respiratory patterns with pyruvate or citrate, but they do exhibit a 30% increase in the rate of citrate export relative to control liver preparations. Paralleling the preferential citrate export from tumor mitochondria is a dramatic enrichment of the tumor mitochondrial membranes with cholesterol. Hepatoma 3924A mitochondria possess a more than 5-fold enrichment in cholesterol, and those from tumor 16 display a 2-fold enrichment. When normal mitochondria, isolated from ACI strain rat liver, were enriched with cholesterol in vitro via a solid-state molecule transfer method employing Sephadex G-10 beads coated with cholesterol, they exhibited altered patterns of Krebs cycle metabolism that were qualitatively identical to those obtained with isolated Morris hepatoma mitochondria (which become enriched in membrane cholesterol endogenously during tumorigenesis). The enrichment of mitochondrial membranes with cholesterol, either by experimental manipulation in vitro or during the proliferation of the tumor in the host animal, promotes these metabolic changes directly, apparently by effecting a functional alteration in the operation of the tricarboxylate (citrate) exchange carrier of the inner mitochondrial membrane. These results highlight two related but incompletely understood phenomena as follows: 1) a functionally truncated Krebs cycle in cholesterol-rich tumor mitochondria, and 2) a mechanism for providing higher cytoplasmic levels of precursor metabolite intermediates which help sustain deregulated cholesterogenesis in hepatomas and other malignant neoplasms.

Animals↗