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PubMed1980

Citrate lyase deacetylase of Rhodopseudomonas gelatinosa. Isolation of the enzyme and studies on the inhibition by L-glutamate.

Citrate lyase deacetylase or acetyl-S-(acyl-carrier protein) enzyme thioester hydrolase (acetate) (EC 3.1.2-), was purified 3100-fold with a yield of 3.8% from cell extracts of Rhodopseudomonas gelatinosa. The final enzyme preparation gave a single protein band upon polyacrylamide-gel electrophoresis in the absence or in the presence of sodium dodecylsulfate. The molecular weight of the native enzyme was estimated by gel filtration to be 14 300 +/- 1000. Sodium dodecylsulfate/polyacrylamide gel electrophoresis yielded a molecular weight of 7300 +/- 600 indicating that the enzyme consisted of two subunits. Citrate lyase deacetylase acted as an S-acetyl enzyme thioesterhydrolase because it catalyzed the conversion of citrate lyase (S-acetyl form) into citrate lyase (sulfhydryl form) and acetate. Citrate lyase deacetylase was strongly inhibited by L-glutamate. The half-maximal inhibitor concentration was 7.5 X 10(-4) M. and a Ki-value of 1.2 X 10(-4) M was determined. The mode of inhibition appeared to be of the linear mixed type. L-Glutamate was bound by citrate lyase deacetylase but not by citrate lyase. The pool concentrations of L-glutamate in R. gelatinosa were 10 mM when citrate was present in substrate amounts and 2.7 mM after total consumption of citrate. Simulation of conditions in vivo using homogeneous enzyme preparations of citrate lyase and citrate lyase deacetylase, and glutamate concentrations of 10 mM and 2.7 mM respectively, revealed that the rate of citrate lyase inactivation increased from 8% within 15 min during growth on citrate to 50% within 15 min in the absence of citrate.

Glutamates↗

PubMed2004

Citrate transport in the human prostate epithelial PNT2-C2 cell line: electrophysiological analyses.

Although prostate synthesizes and releases large amounts of citrate, the mechanism of the release is not well understood. Most known citrate transporters mediate uptake of citrate from extracellular space and, consequently, are driven by the transmembrane Na+ gradient, which would not be appropriate for prostatic function. In the present study, we investigated citrate transport in a normal human prostate cell line, PNT2-C2, using mainly electrophysiological methods. Intracellular application of citrate through the patch pipette in the whole-cell recording mode induced an outward current whilst in response to extracellular citrate an inward current was recorded. Membrane currents induced by citrate were bigger than those elicited by other (equimolar) Krebs cycle intermediates. Both inward and outward citrate-induced currents had the same ionic dependence, inhibitor profile and reversal potential. In particular, the currents were strongly dependent on the transmembrane K+ gradient. Uptake and release of citrate and their K+ dependence were confirmed by spectrophotometric enzyme analyses. Citrate-induced membrane currents were also sensitive to pH, consistent with the transporter preferring the trivalent form. Application of intracellular Zn2+ generated an outward current which had the same quantitative K+ dependence as the citrate-induced currents. Extracellular application of a membrane-permeant Zn2+ chelator generated an inward current. These experiments suggested that m-aconitase was tonically active in PNT2-C2 cells. Determination of 'forward' and 'reverse' K+ stoichiometry both suggested a citrate: K+ ratio of 1: 4. We conclude that normal prostatic epithelial cells possess an electrogenic citrate transporter which mediates the cotransfer of 1 trivalent citrate anion alongside 4 K+ out of cells and thus generates a net outward current.

Carrier Proteins↗

PubMed2002

Identification of a gene cluster in Klebsiella pneumoniae which includes citX, a gene required for biosynthesis of the citrate lyase prosthetic group.

The biosynthesis of the 2'-(5"-phosphoribosyl)-3'-dephospho-coenzyme A (CoA) prosthetic group of citrate lyase (EC 4.1.3.6), a key enzyme of citrate fermentation, proceeds via the initial formation of the precursor 2'-(5"-triphosphoribosyl)-3'-dephospho-CoA and subsequent transfer to apo-citrate lyase with removal of pyrophosphate. In Escherichia coli, the two steps are catalyzed by CitG and CitX, respectively, and the corresponding genes are part of the citrate lyase gene cluster, citCDEFXG. In the homologous citCDEFG operon of Klebsiella pneumoniae, citX is missing. A search for K. pneumoniae citX led to the identification of a second genome region involved in citrate fermentation which comprised the citWX genes and the divergent citYZ genes. The citX gene was confirmed to encode holo-citrate lyase synthase, whereas citW was shown to encode a citrate carrier, the third one identified in this species. The citYZ genes were found to encode a two-component system consisting of the sensor kinase CitY and the response regulator CitZ. Remarkably, both proteins showed >or=40% sequence identity to the citrate-sensing CitA-CitB two-component system, which is essential for the induction of the citrate fermentation genes in K. pneumoniae. A citZ insertion mutant was able to grow anaerobically with citrate, indicating that CitZ is not essential for expression of citrate fermentation genes. CitX synthesis was induced to a basal level under anaerobic conditions, independent of citrate, CitB, and CitZ, and to maximal levels during anaerobic growth with citrate as the sole carbon source. Similar to the other citrate fermentation enzymes, CitX synthesis was apparently subject to catabolite repression.

Amino Acid Sequence↗

PubMed2003

Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients.

OBJECTIVES: To investigate pharmacokinetics and metabolism of sodium citrate in critically ill patients. To determine the risk of citrate accumulation in the setting of liver dysfunction (cirrhosis, hepatorenal syndrome). DESIGN: Prospective cohort study. SETTING: Intensive Care Unit, Department of Medicine IV, University Hospital Vienna. PATIENTS: Consecutive critically ill cirrhotic (n = 16) and noncirrhotic patients (n = 16). INTERVENTIONS: Infusion of sodium citrate (0.5 mmol.kg-1.hr-1) and calcium chloride (0.17 mmol.kg-1.hr-1) for 2 hrs. Analysis of serial arterial blood samples. MEASUREMENTS AND MAIN RESULTS: Total body clearance of citrate was normal in noncirrhotic critically ill patients but significantly reduced in cirrhotic patients (710 vs. 340 mL/min, p =.008). Citrate peak concentrations and concentration over time were increased by 65% and 114% in cirrhotic patients (p <.001), respectively; volumes of distribution were similar. Net metabolic changes were quantitatively similar, with pH and plasma bicarbonate concentrations increasing more slowly in cirrhotic patients. No citrate-related side effects were noted. Citrate clearance could not be predicted by standard liver function tests and was not appreciably influenced by renal function and Acute Physiology and Chronic Health Evaluation II scores. CONCLUSIONS: This first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.

APACHE↗

PubMed2004

Metabolic complications during regional citrate anticoagulation in continuous venovenous hemodialysis: single-center experience.

BACKGROUND: Regional anticoagulation with trisodium citrate is an effective form of anticoagulation for continuous renal replacement therapy (CRRT) in patients at a high risk of bleeding. In a prospective, observational study we compared an established regional citrate anticoagulation protocol [Mehta R et al: Kidney Int 1990;38:976-981] versus a standard heparin anticoagulation protocol focusing on acid-base and electrolyte derangements as well as on cost effectiveness. METHODS AND RESULTS: 209 patients were included in the study. In 37 patients, citrate was used as the sole anticoagulant, 87 patients received low-dose heparin plus citrate, and 85 patients received only heparin as anticoagulant. A customized dialysate solution was used for citrate-anticoagulated CRRT (no buffer, no calcium, reduced sodium concentration). Filter life was significantly higher during citrate anticoagulation compared to heparin anticoagulation (80.2 +/- 60 vs. 30.2 +/- 32 h; p < 0.001). No difference was found between citrate and citrate-heparin anticoagulation (p = 0.310). Metabolic alkalosis was observed in more than 50% of patients on citrate anticoagulation. Alkalosis developed within the first 72 h after initiating treatment and could be reversed in almost all cases by increasing the dialysate flow rate. Hypercalcemia was observed in 13 patients on citrate anticoagulation. Patients with impaired liver function were particularly at risk. Systemic hypocalcemia, hypernatremia, and anion gap acidosis were not observed. Citrate anticoagulation was well tolerated hemodynamically. A longer filter life during citrate anticoagulation translated into a significant cost reduction compared to standard heparin anticoagulation (p < 0.01). CONCLUSION: Regional anticoagulation with trisodium citrate in combination with a customized calcium-free dialysate is a safe and effective alternative to a heparin-based anticoagulation regimen.

Acid-Base Imbalance↗

PubMed1998

Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer.

The prostate gland of humans and many other animals has the major function of accumulating and secreting extraordinarily high levels of citrate. This specialized metabolic process of "net citrate production" is the result of unique metabolic capabilities of the secretory epithelial cells. Most importantly, in prostate cancer (Pca) the capability for net citrate production is lost. In addition to citrate, the normal and BPH (benign prostatic hyperplasia) prostate also accumulates the highest levels of zinc in the body. As with citrate, in Pca the ability for high zinc accumulation is diminished. These and other correlations between zinc and citrate in the prostate have been indicative of an important role of zinc in the regulation of citrate metabolism in normal and malignant prostate epithelial cells. The link between zinc and citrate metabolism has now been established. The intramitochondrial accumulation of high zinc levels inhibits mitochondrial (m-) aconitase activity, which inhibits citrate oxidation. This essentially truncates the Krebs cycle and markedly decreases the cellular energy (ATP) production normally coupled to citrate oxidation. It is also clear that zinc accumulation in citrate-producing prostate epithelial cells is regulated by testosterone and by prolactin. These relationships form the basis for a new concept of the role of zinc and citrate-related energy metabolism in prostate malignancy. The inability of malignant prostate cells to accumulate high zinc levels results in increased citrate oxidation and the coupled ATP production essential for the progression of malignancy. The concept offers new approaches to the treatment of Pca.

Aconitate Hydratase↗

PubMed1987

Inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro.

Effect of citrate on the spontaneous precipitation of calcium oxalate was examined in synthetic media. Citrate significantly increased the formation product of calcium oxalate. This "direct" measure of inhibitor activity, representing activity product at the point of nucleation, rose by 76% by the addition of citrate sufficient to provide trivalent citrate concentration of 1.49 mM. Moreover, citrate inhibited calcium oxalate crystallization by complexing calcium and lowering calcium oxalate saturation. This "indirect" measure of inhibitor activity was assessed from the concentration product of calcium oxalate at the point of nucleation, since this measure should provide a reflection of both ion pair formation and direct inhibitor activity of citrate. The concentration product exceeded the formation product at all ionic (trivalent) citrate concentrations, particularly at high ionic citrate levels. At the ionic citrate concentration of 1.49 mM, the rise in the concentration product was 373%, which was nearly fivefold that observed for the formation product. The presence of ferric or aluminum cations at a physiologic concentration of 2 mg/l did not modify the increase in formation product produced by citrate. Thus, citrate inhibits calcium oxalate crystallization, largely by complexing citrate, but also by directly affecting nucleation. Presence of ferric or aluminum cations at a physiological concentration does not modify the inhibitor action of citrate.

Calcium Oxalate↗

PubMed1998

Net efflux of citrate in Penicillium simplicissimum is mediated by a transport protein.

Penicillium simplicissimum excreted citrate, isocitrate, and succinate when grown in a strongly buffered medium [1 M Mes (pH 6) or 1 M Hepes (pH 7.3)]. Growth in a weakly buffered medium did not lead to citrate excretion despite a similar intracellular citrate concentration. When nongrowing, citrate-excreting hyphae were aerated in a glucose solution, the following steady-state intracellular concentrations of organic acids were measured: succinate (25 mM); citrate, isocitrate, malate, and fumarate (all less than 5 mM). After 2 h of incubation, the extracellular concentrations of these acids were [micromol (g dry wt.)-1]: isocitrate [100], citrate [60], succinate [30], and malate, fumarate, and alpha-ketoglutarate [<5]. The excretion of citrate was due neither to an unspecific change in the permeability of the plasma membrane nor to simple diffusion of undissociated citric acid. The involvement of a transport protein in citrate excretion was indicated because N-ethylmaleimide and sodium azide inhibited citrate excretion strongly despite an unchanged outward-directed citrate gradient. Arguments are given why efflux via a citrate uptake carrier is not considered probable. These results indicate that citrate is excreted by P. simplicissimum via a transport protein that probably specifically mediates the efflux of citrate.

Azides↗

PubMed1996

Prolactin specifically regulates citrate oxidation and m-aconitase of rat prostate epithelial cells.

The prostate gland of many animals, including humans, produces and secretes extremely high levels of citrate. To achieve this function, prostate secretory epithelial cells possess unique metabolic properties that permit accumulation and ultimate secretion (net citrate production) of citrate. Mounting evidence continues to support the concept that prostate epithelial cells possess a limiting mitochondrial (m)-aconitase activity that minimizes citrate oxidation and results in the accumulation of citrate synthesized by the cells. Recent studies have revealed that prolactin (PRL) stimulates net citrate production of rat lateral prostate (RLP). The mechanism of this PRL effect has not been established. The current studies were concerned with the possibility that PRL might be involved in the regulation of citrate oxidation and m-aconitase of prostate cells. Studies were conducted with RLP, RVP (rat ventral prostate), RDP (rat dorsal prostate), and kidney cells. The results showed that PRL in vitro and in vivo decreased citrate utilization and the level of m-aconitase in RLP cells, and conversely increased citrate utilization and m-aconitase in RVP cells. Furthermore, PRL had no effect on either RDP or kidney cells. The effects of PRL on both citrate utilization and m-aconitase of RLP and RVP were abolished by cycloheximide and actinomycin. Mitochondrial studies revealed that PRL decreased citrate oxidation of RLP and increased citrate oxidation of RVP, but had no effect on isocitrate oxidation. In conclusion, these studies establish that PRL has a physiological role in the regulation of citrate oxidation in prostate, and that this action is associated with PRL regulation of the biosynthesis of m-aconitase. Furthermore, the effects of PRL are cell-specific and targeted at m-aconitase.

Aconitate Hydratase↗

PubMed1995

Urinary Tamm-Horsfall protein increased after potassium citrate therapy in calcium stone formers.

OBJECTIVES: To evaluate the effect of oral potassium citrate therapy on urinary excretion rates of citrate. Tamm-Horsfall protein (THP), and on calcium oxalate monohydrate crystal agglomeration inhibition [tm], in patients with recurrent calcium stone formation. METHODS: To evaluate the effect of oral therapy with potassium citrate on urinary citrate, THP, and [tm], 24-hour urine samples were collected before and at least 2 months after initiation of oral potassium citrate therapy in 33 calcium stone-forming patients who had no dietary restrictions. The citrate concentration was measured by an adaptation of a citrate lyase method. Urinary disaggregated THP concentration was determined with a quantitative enzyme-linked immunosorbent assay. The [tm] was determined by observing the effects of patients' urine, before and after oral potassium citrate therapy, on the uptake of 45Ca2+ onto the surfaces of added preformed calcium oxalate crystals in a supersaturated solution of calcium oxalate, using the in vitro kinetic method described by other investigators. RESULTS: We observed an increased urinary excretion rate of citrate from a mean of 1.9 mmol/24 h prealkali to 2.6 mmol/24 h postalkali (P < 0.0004) and of THP from a mean of 94.0 mg/24 h prealkali to 199.3 mg/24 h postalkali (P < 0.0016). A corresponding increase in [tm] from a mean of 177.1 minutes prealkali to 221.0 minutes postalkali (P < 0.024) was also observed. CONCLUSIONS: To our knowledge this is the first report correlating increased urinary citrate with THP excretion rate following oral alkalinization with potassium citrate in calcium stone formers. Of clinical importance is the corresponding increase in [tm], which was previously shown to be inversely related to stone-forming activity. Moreover, urinary citrate and THP are known to have a synergistic effect on [tm]. Our data suggest that the effectiveness of potassium citrate therapy in calcium stone-forming patients may, at least in part, be due to increased levels of THP.

Adult↗

PubMed2005

Citrate kinetics in patients receiving long-term hemodialysis therapy.

BACKGROUND: Regional anticoagulation using sodium citrate is used increasingly in hemodialysis patients at high risk for bleeding. However, citrate metabolism has never been evaluated systematically in hemodialysis patients, and it remains to be shown that citrate is cleared adequately in the presence of renal dysfunction. This study compares the pharmacokinetics of citrate in hemodialysis patients with minimal residual function with that in patients with normal renal function. METHODS: Long-term hemodialysis patients (n = 7) and patients without renal failure (n = 11) were investigated during routine immunoadsorption treatment by using a standardized citrate infusion protocol. Serial analysis of blood samples was performed before, during, and up to 120 minutes after citrate infusion (0.33 mmol/kg/h). Citrate plasma concentrations were measured colorimetrically. In addition, ionized calcium, pH, and bicarbonate were measured by using a blood gas analyzer. RESULTS: Basal (0.09 +/- 0.03 versus 0.12 +/- 0.03 mmol/L; P = not significant) and peak citrate concentrations were similar in both groups (1.24 +/- 0.42 versus 1.19 +/- 0.33 mmol/L; P = not significant). Citrate clearance was similar in patients with renal failure (0.31 +/- 0.06 L/min) and controls (0.35 +/- 0.11 L/min; P = 0.47). Effects on pH were minimal and did not differ between groups. No patient developed complications from citrate infusion. CONCLUSION: Compared with controls, citrate clearance and metabolism in long-term hemodialysis patients is not impaired, and no significant acid-base disorder occurred during citrate anticoagulation. From these data, it is tempting to conclude that citrate anticoagulation can be used safely in patients with chronic renal failure on regular hemodialysis therapy.

Acid-Base Imbalance↗

PubMed1995

Membrane potential-generating transport of citrate and malate catalyzed by CitP of Leuconostoc mesenteroides.

Citrate uptake in Leuconostoc mesenteroides subsp. mesenteroides 19D is catalyzed by a secondary citrate carrier (CitP). The kinetics and mechanism of CitP were investigated in membrane vesicles of L. mesenteroides. The transporter is induced by the presence of citrate in the medium and transports both citrate and malate. In spite of sequence homology to the Na(+)-dependent citrate carrier of Klebsiella pneumoniae, CitP is not Na(+)-dependent, nor is CitP Mg(2+)-dependent. The pH gradient (delta pH) is a driving force for citrate and malate uptake into the membrane vesicles, whereas the membrane potential (delta psi) counteracts transport. An inverted membrane potential (inside positive) generated by thiocyanide diffusion can drive citrate and malate uptake in membrane vesicles. Analysis of the forces involved showed that a single unit of negative charge is translocated during transport. Kinetic analysis of citrate counterflow at different pH values indicated that CitP transports the dianionic form of citrate (Hcit2-) with an affinity constant of approximately 20 microns. It is concluded that CitP catalyzes Hcit2-/H+ symport. Translocation of negative charge into the cell during citrate metabolism results in the generation of a membrane potential that contributes to the protonmotive force across the cytoplasmic membrane, i.e. citrate metabolism in L. mesenteroides generates metabolic energy. Efficient exchange of citrate and D-lactate, a product of citrate/carbohydrate co-metabolism, is observed, suggesting that under physiological conditions, CitP may function as an electrogenic precursor/product exchanger rather than a symporter. The mechanism and energetic consequences of citrate uptake are similar to malate uptake in lactic acid bacteria.

Bacterial Proteins↗

PubMed1993

Gastric anti-secretory, mucosal protective, anti-pepsin and anti-Helicobacter properties of ranitidine bismuth citrate.

Ranitidine bismuth citrate is a novel compound formed from ranitidine and a bismuth citrate complex. In conscious dogs, ranitidine bismuth citrate had similar activity to ranitidine hydrochloride as an inhibitor of histamine-induced gastric acid secretion when oral doses containing equivalent amounts of ranitidine base (0.1 or 0.3 mg/kg) were compared. In the rat, ranitidine bismuth citrate (3-30 mg/kg p.o.) prevented gastric mucosal damage induced by ethanol (fundic damage) and indomethacin (antral damage). Ranitidine hydrochloride and tripotassium dicitrato bismuthate were also effective against indomethacin-induced damage, but were both significantly less potent than ranitidine bismuth citrate in this model. Ranitidine hydrochloride was inactive against ethanol-induced damage. In vitro, ranitidine bismuth citrate (1 mmol/L) inhibited human pepsin isoenzymes 1, 2, 3 and 5. Pepsin 1 was inhibited to a similar extent by ranitidine bismuth citrate, bismuth citrate and tripotassium dicitrato bismuthate at concentrations equivalent to 1 mmol/L bismuth, but ranitidine (1 mmol/L) was inactive. Ranitidine bismuth citrate was more potent than tripotassium dicitrato bismuthate as an inhibitor of pepsins 2, 3 and 5. Ranitidine bismuth citrate inhibited both Helicobacter pylori (effective concentration 4-32 micrograms bismuth/ml) and H. mustelae (1-4 micrograms bismuth/ml); similar results were obtained with tripotassium dicitrato bismuthate. Bismuth citrate was slightly less effective, and ranitidine hydrochloride was inactive (> 125 micrograms/ml). In ferrets naturally colonized with H. mustelae, oral treatment with ranitidine bismuth citrate, 12 or 24 mg/kg twice daily for 4 weeks, caused a dose related clearance of H. mustelae. Qualitatively similar results were obtained in a small study with tripotassium dicitrato bismuthate and bismuth citrate.

Animals↗

PubMed1983

Citrate utilization by Escherichia coli: plasmid- and chromosome-encoded systems.

Citrate utilization plasmids have previously been identified in atypical Escherichia coli isolates. A different citrate-utilizing (Cit+) variant of E. coli K-12 arose as a consequence of two chromosomal mutations (B. G. Hall, J. Bacteriol. 151:269-273, 1982). The processes controlling the transport of citrate in both a Cit+ chromosomal mutant and a Cit+ plasmid system were studied. Both systems were found to be inducible in growth experiments. In transport assays with whole cells, citrate-grown cells accumulated [1,5-14C]citrate at two to three times the rate of uninduced cells. Only the Vmax was affected by induction, and the Km for whole cells remained at 67 microM citrate for the chromosomal strain and 120 microM citrate for the plasmid-conferred system. There was no detectable accumulation of radioactivity with [6-14C]citrate, because of rapid metabolism and the release of 14CO2. Energy-dependent citrate transport was found with membrane vesicles obtained from both the chromosome-conferred and the plasmid Cit+ systems. The vesicle systems were inhibited by valinomycin and carbonyl cyanide m-chloro-phenylhydrazone but not by nigericin and monensin. In contrast to whole cells, the vesicle systems were resistant to Hg2+ and showed identical kinetics with [1,5-14C]citrate and [6-14C]citrate. H+ appeared to be important for citrate transport in whole cells and membranes. Monovalent cations such as Na+ and K+, divalent cations such as Mg2+ and Mn2+, and anions such as PO4(3-), SO4(2-), and NO3- were not required. The two systems differed in inhibition by citrate analogs.

Aconitic Acid↗

PubMed1967

Regulation of renal citrate metabolism by bicarbonate ion and pH: observations in tissue slices and mitochondria.

The effect of acid-base balance on the oxidation and utilization of citrate and other organic acids has been studied in tissue slices and isolated kidney mitochondria. The results show that: 1) With bicarbonate-buffered media, citrate oxidation and utilization are inhibited in slices of renal cortex and in kidney mitochondria when [HCO(3) (-)] and pH are increased within the physiologic range (pH 7.0 to 7.8; 10 to 60 mumoles HCO(3) (-) per ml). When phosphate or Tris buffers are used, no comparable effect on citrate oxidation occurs when pH is varied. 2) This effect is not demonstrable in heart or liver slices when a physiologic buffer is used. 3) alpha-Ketoglutarate utilization is inhibited in slices of renal cortex under similar conditions. Pyruvate and L-malate utilization are not inhibited in slices or mitochondria. 4) Citrate content in slices of renal cortex incubated with a high [HCO(3) (-)] is considerably greater than the concentration found with a low [HCO(3) (-)] in the medium. This effect is not duplicated by pH change in a nonbicarbonate buffer system. In mitochondria citrate content is also increased markedly at high bicarbonate concentrations. 5) The kinetic characteristics of the inhibition of citrate oxidation are those of a competitive type of inhibition. 6) When pH was varied with a constant [HCO(3) (-)] in the media, citrate oxidation was inhibited by increasing pH in slices of renal cortex but not in mitochondria. On the other hand, when [HCO(3) (-)] was increased without change in pH, no decrease in citrate oxidation occurred in slices, but a marked inhibitory effect was found when mitochondria were used. From a comparison of these results with those previously obtained in intact animal experiments, we conclude that the inhibition of citrate oxidation caused by increasing pH and [HCO(3) (-)] in slices of renal cortex and kidney mitochondria is an in vitro representation of the inhibition of citrate reabsorption in the nephron that occurs in metabolic alkalosis. Thus, citrate clearance increases in metabolic alkalosis because of inhibition of oxidation of reabsorbed citrate within cells of the renal tubules. This inhibition is the result of an inhibitory effect of bicarbonate ion on citrate oxidation in mitochondria.

Alkalosis↗

PubMed1991

Renal excretion of citrate in patients with chronic renal failure or nephrolithiasis.

Using a specific citrate lyase method, renal excretion of citrate was studied in 32 normal Chinese males, 30 nondialysed uremic male patients and 35 male subjects who had a history of nephrolithiasis. Patients with uremia or nephrolithiasis were found to have a lower urinary citrate excretion. Tubular reabsorption of citrate was markedly decreased in uremic patients, but in stone patients, the increased renal tubular reabsorption of citrate was only found in patients with hypocitraturia, whose renal citrate excretion was below 650 mumol/day and whose urinary magnesium was also low. Hypocitraturia was found in 45% (16/35) of the patients with renal stones whether their filtered load of citrate was normal or subnormal. Urinary citrate excretion was correlated with renal creatinine clearance in both normal subjects and in patients with renal stones or chronic renal failure. However, urinary phosphate correlating with urinary citrate was only found in normal subjects and in patients with kidney stones. In normal subjects, we found a positive correlation between urinary citrate and phosphate, but in stone patients, we found a negative correlation. Hypercalciuria and hyperoxalaturia were noted in some stone formers, who had, moreover, a lower urinary citrate and ascorbate excretion level. Mean urinary ascorbate excretion in patients with renal stones was markedly below that in normal subjects. Thus, we suggest that low urinary citrate excretion may be prevalent in patients with renal stones or chronic renal failure, and that hypocitraturia can be found in some stone formers, whose tubular reabsorption of citrate may be increased.

Adult↗

PubMed1988

The effects of oral or intravenous citrate on the activation of neutrophils in vitro.

Topical citrate has been shown to significantly reduce the severity and incidence of corneal ulceration in alkali-burned rabbit eyes. Subcutaneous injection of citrate significantly reduced the severity of ulceration. This study was performed to determine the plasma citrate and ionized calcium levels after systemic administration of citrate. Repeated ingestion of citric acid capsules showed a small increase in the plasma citrate level, but no significant change in the level of ionized serum calcium 30 min after the last ingestion. A single dose of Polycitra-LC (6.672 g of citrate) more than doubled the baseline citrate concentration but only induced a 5% decrease in the level of ionized serum calcium 30 min after ingestion. Neither regimen of orally administered citrate produced any significant effect on the respiratory burst or adherence of in vitro polymorphonuclear leukocytes (PMNs) resuspended in their respective plasma. In comparison studies, higher levels of plasma citrate and lower levels of ionized serum calcium were achieved through plateletpheresis. The respiratory burst and adherence of PMNs were not statistically different from baseline PMNs. However, there was an inverse correlation between the micromolar increase in citrate or the micromolar decrease in calcium and the respiratory burst. These results suggest that the use of oral citrate alone may not be practical, but does not preclude the use of oral citrate as a supplement to topical citrate.

Administration, Oral↗

PubMed1993

Effects of citrate on the different phases of calcium oxalate crystallization.

Urinary citrate appears to be an important factor in the crystallization process of calcium oxalate and calcium phosphate. The urinary excretion of citrate was found to be significantly lower in patients with calcium oxalate stone disease as compared with normal subjects, and about 30 per cent of the calcium stone formers can be considered as hypocitraturic. The lowest excretion of citrate was recorded in urine collected during the night. Citrate has significant effects on supersaturation with respect to both calcium oxalate and calcium phosphate, it also inhibits the growth of these crystals. In addition, citrate appears to be capable of inhibiting the aggregation of crystals composed of calcium oxalate, brushite, and hydroxyapatite. The heterogenous growth of calcium oxalate on calcium phosphate is also counteracted by citrate. As a consequence of the crucial role of citrate in these processes, stone prevention with alkaline citrate has become an attractive form of treatment in patients with recurrent stone formation. Single evening dose administration of sodium potassium citrate resulted in an of sodium potassium citrate resulted in an increased excretion of citrate, reduced levels of the calcium/citrate ratio as well as supersaturation with respect to calcium oxalate and a decreased rate of stone formation. However, conflicting results of stone preventive treatment with alkaline citrate have been reported by different groups, and long-term follow-up of patients treated in a randomized way is necessary to definitely assess the efficacy of alkaline citrate.

Calcium Oxalate↗