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PubMed1996

Glycerol is not an inhibitor of mitochondrial citrate oxidation by Aspergillus niger.

We have re-assessed the hypothesis that an accumulation of intracellular glycerol triggers the accumulation of citric acid by Aspergillus niger by inhibiting the activity of the mitochondrial NADP-dependent isocitrate dehydrogenase isoenzyme. To this end, we have incubated mycelia of A. niger with 0.5 M glycerol, which resulted in a maximal intracellular glycerol pool level of 0.92 M, comparable to that determined during the early phase of citrate accumulation. This addition affected neither the uptake of [1,5-14C] citrate from the medium nor the rate of the subsequent release of 14CO2 by the mycelia, indicating no effect on citrate oxidation. Mitochondria isolated from mycelia previously loaded with 0.5 M glycerol contained 8% of the total mycelial glycerol. They released 14CO2 from exogenously added [1,5-14C]citrate at the same rate as mitochondria isolated from mycelia not loaded with 0.5 M glycerol. The addition of glycerol had no effect on the activity of the purified NADP-specific isocitrate dehydrogenase, but appeared to inhibit the activity in crude cell-free extracts of A. niger. We conclude that the intracellular accumulation of glycerol does not affect the rate of mitochondrial citrate oxidation and is therefore, in contrast to previous claims, not a trigger of citrate accumulation.

Aspergillus niger↗
PubMed2004

Citrate-permeable channels in the plasma membrane of cluster roots from white lupin.

White lupin (Lupinus albus) is well adapted to phosphorus deficiency by developing cluster roots that release large amounts of citrate into the rhizosphere to mobilize the sparingly soluble phosphorus. To determine the mechanism underlying citrate release from cluster roots, we isolated protoplasts from different types of roots of white lupin plants grown in phosphorus-replete (+P) and phosphorus-deficient (-P) conditions and used the patch-clamp technique to measure the whole-cell currents flowing across plasma membrane of these protoplasts. Two main types of anion conductance were observed in protoplasts prepared from cluster root tissue: (1) an inwardly rectifying anion conductance (IRAC) activated by membrane hyperpolarization, and (2) an outwardly rectifying anion conductance (ORAC) that became more activated with membrane depolarization. Although ORAC was an outward rectifier, it did allow substantial inward current (anion efflux) to occur. Both conductances showed citrate permeability, with IRAC being more selective for citrate3- than Cl- (PCit/PCl = 26.3), while ORAC was selective for Cl- over citrate (PCl/PCit = 3.7). Both IRAC and ORAC were sensitive to the anion channel blocker anthracene-9-carboxylic acid. These currents were also detected in protoplasts derived from noncluster roots of -P plants, as well as from normal (noncluster) roots of plants grown with 25 microm phosphorus (+P). No differences were observed in the magnitude or frequency of IRAC and ORAC currents between the cluster roots and noncluster roots of -P plants. However, the IRAC current from +P plants occurred less frequently than in the -P plants. IRAC was unaffected by external phosphate, but ORAC had reduced inward current (anion efflux) when phosphate was present in the external medium. Our data suggest that IRAC is the main pathway for citrate efflux from white lupin roots, but ORAC may also contribute to citrate efflux.

Calcium↗
PubMed1995

Regulation of citrate-dependent iron transport of Escherichia coli: fecR is required for transcription activation by FecI.

Citrate-dependent Fe3+ transport into Escherichia coli K-12 is induced by iron and citrate. The inducer is probably ferric dicitrate which does not have to be taken up into the cytoplasm to induce transcription of the fec transport genes. Two regulatory genes, fecI and fecR, located upstream of the fecABCDE transport genes, are required for induction. We report that in vivo the chromosomally encoded FecI protein activates transcription of the fecA and fecB transport genes in response to ferric citrate and the FecR protein. Cells expressing chromosomally and plasmid-encoded truncated FecR derivatives no longer responded to ferric citrate and expressed the fec transport genes constitutively. The smallest active FecR derivative contained 59 amino acid residues as compared to the 317 residues of wild-type FecR. Constitutive induction was lower than induction of the FecR wild-type strain by ferric citrate. It is concluded that the N-terminal portion of FecR activates FecI and that the C-terminal portion of FecR responds to ferric citrate. Transcription of the fec transport genes is positively regulated by FecI and FecR and negatively regulated by the Fe2(+)-Fur repressor. Transcription activation and repression may occur independently of each other.

Amino Acid Sequence↗
PubMed2005

Citrate anticoagulation for single-needle hemodialysis: safety and efficacy.

Single-needle hemodialysis can be the only option in some patients and requires full heparinization. The aim of our retrospective clinical study was to evaluate the safety and efficacy of regional citrate anticoagulation for single-needle hemodialysis. Citrate anticoagulation was performed during 41 single-needle hemodialysis procedures in 24 patients at risk of bleeding, using 4% trisodium citrate, 1 M CaCl2 and calcium-free dialysate. Safety was assessed by the percentage of procedures that were terminated prematurely or changed to another modality due to citrate-related complications and by incidence of important hypocalcemia. Efficacy was evaluated by visually assessing clot formation in the circuit. Five per cent of the procedures were terminated prematurely. Important hypocalcemia was recorded in 34% of the procedures. Anticoagulation was suboptimal in 17% of the procedures, but none of the systems clotted. The median dialyzer assessment grade was excellent. The average protocol parameters were: blood flow 244 +/- 27 mL/min, starting rate of citrate 191 +/- 19 mL/h, starting rate of calcium 6.7 +/- 1.1 mL/h. In the first hour, ionized calcium decreased in 67% of the procedures by 0.08 +/- 0.05 mmol/L. During the entire procedure, ionized calcium decreased in 80% of the cases by 0.17 +/- 0.09 mmol/L. There was a significant, but small increase in sodium (135 +/- 4 vs 137 +/- 4 mmol/L) and no increase in bicarbonate. Citrate anticoagulation during single-needle hemodialysis, according to our protocol, is safe and effective. Close monitoring of ionized calcium is mandatory. The calcium infusion rate should frequently be increased to correct hypocalcemia. The increased starting rate of calcium should be evaluated.

Aged↗
PubMed1998

Distribution of bismuth in the rat after oral dosing with ranitidine bismuth citrate and bismuth subcitrate.

Bismuth preparations are used world-wide for the management of peptic ulcer disease, for eradication of Helicobacter pylori, and in the prevention and treatment of diarrhoea. However neurological toxicity of bismuth has always been a major concern and evidence has been found of the absorption of bismuth. Recent studies have suggested that the absorption of bismuth increases when bismuth salts are used with ranitidine hydrochloride. The absorption and deposition of bismuth as a result of the use of the new drug ranitidine bismuth citrate have not been yet clarified. After 15 days of twice daily oral gavage with bismuth subcitrate, 13.7 mg kg(-1) day(-1) to eight rats, deposition of bismuth was found in all the tissues studied, especially the kidney (30.81 +/- 8.59 microg g(-1) dry weight). A similar pattern of distribution and tissue concentrations was found when bismuth subcitrate was given with ranitidine hydrochloride 8.6 mg kg(-1) day(-1) to another eight rats, although this combination resulted in lower brain levels (3.12 + 1.31 microg g(-1) dry weight) than after administration of bismuth subcitrate alone (4.77 +/- 0.97 microg g(-1) dry weight). When six rats were given ranitidine bismuth citrate by gavage at 22.8 mg kg(-1) day(-1) for 15 days, kidney levels were lower (4.24 +/- 1.75 microg g(-1) dry weight) and brain levels were below detection limits; the bismuth concentrations in the faeces from this group were also significantly lower (1603 +/- 104.0 microg g(-1) dry weight) than for the two other groups. After dosing with bismuth alone or in association with ranitidine hydrochloride, bismuth was detected in several organs and deposition was not influenced by gastric pH. Blood levels correlate poorly with organ deposition and brain deposition was not always associated with encephalopathy. After administration of ranitidine bismuth citrate, significantly lower concentrations of bismuth were found in the kidney and bismuth was not detectable in the brain, suggesting lower bismuth absorption. This was confirmed by higher levels in the faeces after dosing with ranitidine bismuth citrate. Thirty days after dosing with ranitidine bismuth citrate or bismuth subcitrate, bismuth could not be detected in any of the organs examined but could be found in the urine. In conclusion, bismuth was deposited in the kidney, brain, lung and liver of rats after oral dosing with bismuth subcitrate. After oral dosing with an equivalent amount of bismuth in the form of ranitidine bismuth citrate, significantly lower concentrations of bismuth were deposited in the kidney; in the brain bismuth was not detectable.

Administration, Oral↗
PubMed1979

Characterization of Plasmid Deoxyribonucleic Acid in Streptococcus lactis subsp. diacetylactis: Evidence for Plasmid-Linked Citrate Utilization.

The use of Streptococcus diacetylactis as a flavor producer in dairy fermentations is dependent upon its ability to produce diacetyl from citrate. Treatment of S. diacetylactis strains 18-16 and DRC1 with acridine orange resulted in the conversion of approximately 2% of the DRC1 population and 20% of the 18-16 population to citrate negative, which is indicative of the involvement of plasmid deoxyribonucleic acid (DNA). Growth in the presence of acridine orange also resulted in the appearance of 2% lactose-negative derivatives in S. diacetylactis 18-16 and 99% lactose-defective, proteinase-negative derivatives in S. diacetylactis DRC1. Cesium chloride-ethidium bromide equilibrium density gradients of cleared lysate material from each strain revealed the presence of covalently closed circular DNA. Samples of this covalently closed circular DNA were subjected to agarose gel electrophoresis to determine the plasmid composition of each strain. S. diacetylactis 18-16 was found to possess six plasmids, of approximately 41, 28, 6.4, 5.5, 3.4, and 3.0 megadaltons (Mdal). S. diacetylactis DRC1 contained six plasmids, of approximately 41, 31, 18, 5.5, 4.5, and 3.7 Mdal. Variants of S. diacetylactis 18-16 which failed to produce acetoin plus diacetyl from citrate (citrate negative) were missing a 5.5-Mdal plasmid. Lactose-negative mutants of the same strain were devoid of a 41-Mdal plasmid. Lactose-defective, proteinase-negative mutants of S. diacetylactis DRC1 were missing a 31-Mdal plasmid. The citrate-negative mutants of S. diacetylactis DRC1 isolated in this study did not possess a 5.5-Mdal plasmid. Thus, we have evidence that there is a correlation between the ability to utilize citrate and the presence of a 5.5-Mdal plasmid. A relationship was also noted between lactose fermentation and proteinase activity and plasmid DNA in S. diacetylactis.

Journal Article↗
PubMed1980

Effect of titanium (III) citrate as reducing agent on growth of rumen bacteria.

We compared the growth of 10 strains of rumen bacteria in an anaerobic medium reduced with cysteine hydrochloride, dithiothreitol, or titanium (III) citrate. The redox potential of medium reduced with cysteine hydrochloride was -167.8 mV; with dithiothreitol it was -175.8 mV; and with titanium(III) citrate it was -302.4 mV at a concentration of 5 X 10(-4) M titanium and -403.9 mV at 2 X 10(-3) M titanium. Maximum growth of the strains was generally lower with dithiothreitol or titanium(III) citrate than with cysteine hydrochloride, although growth was greater than in medium lacking an added reducing agent. Strains for which cysteine was required or markedly stimulatory grew only poorly with titanium(III) citrate. No strain grew in medium with sodium citrate as the energy source. Titanium(III) citrate could be used to reduce anaerobic media for some rumen bacteria if the exclusion of a sulfur-containing reducing agent is required.

Anaerobiosis↗
PubMed1981

Ferric citrate transport in Escherichia coli requires outer membrane receptor protein fecA.

Mutants of Escherichia coli K-12 AB2847 and of E. coli K-12 AN92 were isolated which were unable to grow on ferric citrate as the sole iron source. Of 22 mutants, 6 lacked an outer membrane protein, designated FecA protein, which was expressed by growing cells in the presence of 1 mM citrate. Outer membranes showed an enhanced binding of radioactive iron, supplied as a citrate complex, depending on the amount of FecA protein. The FecA protein was the most resistant of the proteins involved in ferric irion iron translocation across the outer membrane (FhuA = TonA, FepA, Cir, or 83K proteins) to the action of pronase P. It is also shown that previously isolated fec mutants (G. C. Woodrow et al., J. Bacteriol. 133:1524-1526, 1978) which are cotransducible with argF all lack the FecA protein. They were termed fecA to distinguish them from the other ferric citrate transport mutants, now designated fecB, which mapped in the same gene region at 7 min but were not cotransducible with ArgF. E. coli W83-24 and Salmonella typhimurium, which are devoid of a citrate-dependent iron transport system, lacked the FecA protein. It is proposed that the FecA protein participates in the transport of ferric citrate.

Bacterial Proteins↗
PubMed1998

Ferric citrate transport of Escherichia coli: functional regions of the FecR transmembrane regulatory protein.

Transcription of the ferric citrate transport genes of Escherichia coli is induced by ferric citrate bound to the outer membrane receptor FecA. Additional ferric citrate-specific regulatory proteins are FecR in the cytoplasmic membrane and the FecI sigma factor in the cytoplasm. To further understand the assumed FecR-mediated signal transduction across the cytoplasmic membrane, the transmembrane topology of FecR (317 amino acids) was determined with hybrid proteins containing portions of FecR and mature BlaM beta-lactamase. BlaM fused to FecR regions extending from residues 107 to 149 and residues 230 to 259 conferred high ampicillin resistance to cells, while BlaM fused to sites between residues 159 and 210 and between residues 265 and 301 conferred low resistance. Cells that synthesized FecR'-BlaM with fusion joints between residues 8 and 81 of FecR were fully sensitive to ampicillin. The ampicillin resistance of the low-resistance FecR'-BlaM hybrids was increased 2- to 10-fold by cosynthesis of plasmid-encoded GroEL GroES and SecB chaperones and in degP and ompT protease mutants, which suggested that the decreased ampicillin resistance level of these hybrids was caused by the formation of inclusion bodies and proteolytic degradation. Replacement of glycine by aspartate residues in the only hydrophobic FecR sequence (residues 85 to 100) abolished the beta-lactamase activity of high-resistance FecR'-BlaM proteins, indicating that there are no other transmembrane regions in FecR that translocate BlaM into the periplasm independent of the hydrophobic sequence. All FecR'-BlaM proteins with at least 61 FecR residues complemented a fecR mutant such that it could grow on ferric citrate as the sole iron source and induced fecA-lacZ transcription independent of ferric citrate. The low resistance mediated by two FecR'-BlaM proteins in a fecA deletion mutant was increased 20-fold by transformation with a fecA-encoding plasmid. We propose that FecR spans the cytoplasmic membrane once, interacts in the periplasm with its C-terminal region with FecA occupied by ferric citrate, and transmits the information through the cytoplasmic membrane into the cytoplasm, where it converts FecI into an active sigma factor.

Amino Acid Sequence↗
PubMed1997

Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate.

BACKGROUND: Integrilin (eptifibatide), a potent inhibitor of the fibrinogen binding function of GP IIb-llla, has been shown to reduce the thrombotic complications of angioplasty and of acute coronary syndromes. The present study was designed to determine whether the reduced Ca2+ concentrations in plasma anticoagulated with citrate affect Integrilin binding to GP IIb-IIIa and the ex vivo pharmacodynamic measurements for this drug. METHODS AND RESULTS: Lower concentrations of Integrilin were found to inhibit platelet aggregation in plasma anticoagulated with citrate (for ADP, mean+/-SD IC(50)=140+/-40 nmol/L, n=6; Ca2+ =40 to 50 micromol/L) than with PPACK (IC(50)=570+/-70 nmol/L, P<.0001, n=6; Ca2+ approximately 1 mmol/L). Chelation of Ca2+ with EDTA or citrate caused a similar degree of enhancement in the inhibitory activity of Integrilin. Measurements of D3 LIBS epitope expression showed that the enhanced inhibitory activity was caused by enhanced GP IIb-IIIa occupancy by Integrilin. Citrate anticoagulation decreased the amounts of Integrilin required to inhibit the binding of PAC1, a monoclonal antibody that mimics the GP IIb-IIIa binding activity of fibrinogen. Reduced Ca2+ also increased Integrilin inhibition of the binding of biotinylated fibrinogen to purified, immobilized GP IIb-IIIa. CONCLUSIONS: These data suggest that citrate anticoagulation removes Ca2+ from GP IIb-IIIa and enhances the apparent inhibitory activity of Integrilin. This finding indicates that the inhibitory activity of Integrilin is overestimated in blood samples collected with citrate, suggesting that it may be possible to achieve greater antithrombotic efficacy beyond that observed in clinical trials to date with Integrilin.

Antibodies, Monoclonal↗
PubMed1981

Cyclic clomiphene citrate treatment lowers cytosol estrogen and progestin receptor concentrations in the endometrium of postmenopausal women on estrogen replacement therapy.

Clinical and experimental studies have indicated that a nonsteroidal antiestrogen, clomiphene citrate, might prevent the stimulatory action of estrogens on the human endometrium. To investigate the mechanisms of this effect, the treatment of 19 postmenopausal patients with conjugated estrogens for 6 months was supplemented cyclically for 10 days with clomiphene citrate after every 7 weeks. Ten patients ingested clomiphene citrate alone, whereas 9 patients continued estrogen treatment during clomiphene supplementation. Estrogen and progestin receptors were measured from the cytosol of the endometrium after the first estrogen period and after the first and third clomiphene treatment. The estrogen receptor concentration was significantly lower after both clomiphene supplementation periods than after the initial estrogen administration. The progestin receptor concentration was significantly lower only after the first clomiphene citrate period. The effect of clomiphene citrate was independent of the initial histological appearance of the endometrium and led to atrophy of the endometrium in most of the patients. Because the effect of clomiphene citrate was independent of simultaneous estrogen administration, it acted as a pure antiestrogen in this treatment modality. The relative decreases in estrogen and progestin receptor concentrations on the present treatment regimen were different from those previously found on progestin treatment and most likely occur via different mechanisms. It is not known whether these two treatment types will have additive effects.

Clomiphene↗
PubMed2001

Rectal antinociceptive properties of alverine citrate are linked to antagonism at the 5-HT1A receptor subtype.

Serotonin (5-HT) is considered as a major mediator causing hyperalgesia and is involved in inflammatory reactions and irritable bowel syndrome. Alverine citrate may possess visceral antinociceptive properties in a rat model of rectal distension-induced abdominal contractions. This study was designed to evaluate the pharmacological properties of alverine citrate in a rat model of rectal hyperalgesia induced by 5-HTP (5-HT precursor) and by a selective 5-HT1A agonist (8-OH-DPAT) and to compare this activity with a reference 5-HT1A antagonist (WAY 100635). At 4 h after their administration, 5-HTP and 8-OH-DPAT increased the number of abdominal contractions in response to rectal distension at the lowest volume of distension (0.4 mL). When injected intraperitoneally before 8-OH-DPAT and 5-HTP, WAY 100635 (1 mg kg(-1)) blocked their nociceptive effect, but also reduced the response to the highest volume of distension (1.6 mL). Similarly, when injected intraperitoneally, alverine citrate (20 mg kg(-1)) suppressed the effect of 5-HTP, but not that of 8-OH-DPAT. However, when injected intracerebroventricularly (75 microg/rat) alverine citrate reduced 8-OH-DPAT-induced enhancement of rectal distension-induced abdominal contractions. In-vitro binding studies revealed that alverine citrate had a high affinity for 5-HT1A receptors and a weak affinity for 5-HT3 and 5-HT4 subtypes. These results suggest that 5-HTP-induced rectal hypersensitivity involves 5-TH1A receptors and that alverine citrate acts as a selective antagonist at the 5-HT1A receptor subtype to block both 5-HTP and 8-OH-DPAT-induced rectal hypersensitivity.

5-Hydroxytryptophan↗
PubMed1989

Effects of clomiphene citrate on ovarian function in hypophysectomized rats.

On Days 28-30 of age, hypophysectomized rats were treated with oestradiol-17 beta (0.1 mg/day) and/or clomiphene citrate (0.1 mg/day). Subsequent treatment with PMSG (10 i.u., on Day 31) and hCG (10 i.u., on Day 33) was identical for all animals. Rats were killed on Day 34. Treatment with oestradiol-17 beta alone resulted in ovulations of 45.1 +/- 5.5 oocytes/rat (mean +/- s.e.m.). There were no ovulations among animals treated with clomiphene citrate alone but treatment with oestradiol-17 beta and clomiphene citrate resulted in a significant (P less than 0.05) reduction (23.1 +/- 7.6 oocytes/rat) in ovulatory response. Similarly, ovarian weights and serum progesterone concentrations were highest in the oestradiol-17 beta-treated rats, intermediate in those given oestradiol plus clomiphene citrate and the lowest in rats receiving clomiphene citrate alone. We suggest that clomiphene citrate exerts direct ovarian antiovulatory and oestrogen-antagonist actions.

Animals↗
PubMed2002

Relationship between concentration of citrate and ketone bodies in cow's milk.

The authors' hypothesis is that the members of the tricarboxylic acid cycle (TCA cycle) such as citrate decrease in association with increased ketone body formation. To prove this hypothesis the connection between ketone bodies and citrate formation of milk was studied. A fluorimetric method was used to determine citrate and a headspace sampling gas chromatographic (GC) method was developed for determination of ketone bodies. Under real conditions of milk sampling, transport and storage, preserved milk samples of 119 clinically healthy dairy cows obtained in the 48 hours after milking were investigated. A low level of acetoacetate (ACAC) was found in all samples. This fact can be explained by the spontaneous decarboxylation of acetoacetate during sample storage (previously decarboxylised acetoacetate = pdACAC) and, consequently, the majority of the amount of acetoacetate in the samples (AC + pdACAC) appeared in the measured acetone concentrations. Based on the measured acetone concentration of milk samples two groups were formed retrospectively: HA (high-acetone) group (n = 41) with an AC + pdACAC concentration of > 0.4 mmol/l and a LA (low-acetone) group (n = 78) with an AC + pdACAC level of < or = 0.4 mmol/l. In the milk of cows of Group HA a positive correlation (r = +0.623) and linear connection between acetone (AC + pdACAC) and beta-hydroxybutyrate (BOHB) levels was found [BOHB = 2.491 + 0.586 x (pdAC + ACAC)]. Furthermore, in this group a negative correlation between citrate and BOHB and AC + pdACAC was also established (r = -0.579). Focusing on the results of this group the authors found a significant drop of AC + pdACAC and citrate during the metabolically critical first 1-4 weeks of lactation. For this reason they suggest that simple, easy, automated methods (i.e. flow injection analysis, Fourier transformation infrared analysis) should be introduced for the simultaneous determination of acetone and citrate concentration in milk to make the evaluation of the energy status of high-producing dairy cows easier and more certain.

Animals↗
PubMed2002

Citrate-mediated increase in the uptake of weathered 2,2-bis(p-chlorophenyl) 1,1-dichloroethylene residues by plants.

Experiments were conducted to determine the ability of citrate to enhance the plant uptake of weathered 2,2-bis(p-chlorophenyl)1,1-dichloroethylene (p,p'-DDE) from soil. Plots containing three rows of clover, mustard, hairy vetch, or rye grass were constructed in soils containing p,p'-DDE. On 11 occasions, the rows of each crop received water or sodium citrate (0.005 or 0.05 M). For each crop, there were significant reductions in p,p'-DDE concentration in the soil fractions (near root and rhizosphere) closely associated with the plant versus bulk soil. The roots of each crop accumulated 2 to 5 times more of the weathered contaminant (dry wt) than present in the bulk soil. Citrate (0.05 M) increased the concentration of p,p'-DDE in the roots of clover, mustard, and hairy vetch by 39% compared with vegetation that received water. In batch desorption studies, the release of weathered p,p'-DDE was significantly greater in the presence of 0.05 M citrate than in water. Citrate increased the extracted aqueous concentrations of five metal ions (Al, Fe, Ca, K, Mn) from soil by five- to 23-fold over distilled water. We hypothesize that citrate physically disrupts the soil through chelation of structural metal ions and release of bound humic material, facilitating p,p'-DDE availability and uptake by plants.

Biodegradation, Environmental↗
PubMed2000

Cyclic changes in serum levels of insulin-like growth factor binding protein-1 in women treated with clomiphene citrate and tamoxifen.

In order to investigate the cyclic changes of serum insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 levels in menstrual cycles treated with or without antiestrogens (clomiphene citrate and tamoxifen), we treated 24 young women having irregular menstrual cycles with either clomiphene citrate (100 mg/day) (n = 12) or tamoxifen (60 mg/day) (n = 12) from the 5th to the 9th day of the menstrual cycle. Without antiestrogens, 12 women with regular menstrual cycles were recruited as controls. There was a preovulatory (day 13) peak of circulating IGFBP-1 in women treated with or without antiestrogens. A significant concomitant increase in serum estradiol was also observed on day 13 of the menstrual cycle in subjects treated with clomiphene citrate and in controls. However, no significant elevation in preovulatory estradiol was detected in women treated with tamoxifen. In clomiphene citrate and control groups, a significant positive correlation was found between circulating IGFBP-1 and estradiol, and between serum levels of IGFBP-1 and inhibin A at the preovulatory stage (on day 13). In contrast, no such association was observed in the tamoxifen group. Unlike cyclic changes in circulating IGFBP-1, serum concentrations of IGF-I and IGFBP-3 remained unchanged throughout the menstrual cycle in all groups. In conclusion, the preovulatory peak of circulating IGFBP-1 can be induced in cycles treated with both clomiphene citrate and tamoxifen. In addition, a significant positive correlation between estradiol, inhibin A and IGFBP-1 at the preovulatory stage indicates that IGFBP-1 may also reflect follicular development and may further be used as an additional indicator to monitor folliculogenesis under clomiphene citrate treatment.

Adult↗
PubMed1993

The effect of clomiphene citrate isomers on human granulosa-lutein cells in culture.

The effect of racemic clomiphene citrate and its two individual isomeric forms (i.e. en and zu) on corpus luteum function was evaluated. Granulosa-lutein cells were obtained from three normal ovulatory women undergoing oocyte retrieval following ovulation induction with agents other than clomiphene citrate for in vitro fertilization--embryo transfer (IVF-ET). The granulosa cells were cultured in the presence and absence of the three forms of clomiphene citrate, and in the presence and absence of human chorionic gonadotropin (hCG). Patients were recruited from the unit for assisted reproductive technology in a university hospital. The main outcome measured was the production of estradiol and progesterone by cultured human granulosa cells under the various conditions described above. The production of estradiol and progesterone by the cultured granulosa cells was dose-dependently reduced to a similar extent by all three forms of clomiphene citrate. The addition of hCG augmented steroidogenesis in all groups at all concentrations, but this still remained lower in all clomiphene citrate-treated groups compared to controls. The data suggest that all three types of clomiphene citrate (racemic, en, and zu) have inhibitory effects on the production of estradiol and progesterone by cultured human granulosa-lutein cells.

Adult↗
PubMed2006

Variation of milk citrate with stage of lactation and de novo fatty acid synthesis in dairy cows.

Citrate is a normal constituent of milk that affects milk-processing characteristics. It is an intermediate in the tricarboxylic acid cycle and plays an indirect role in fat synthesis by providing reducing equivalents in the form of NADPH. The objective of this study was to investigate variation in citrate with stage of lactation and de novo fatty acid synthesis, without confounding dietary effects. Twenty-four cows were fed the same diet, and milk citrate and fatty acids were determined over a 10-d period. Eight cows were in early lactation [13 +/- 1.8 d in milk (DIM; mean +/-standard error], 8 in midlactation (130 +/-4.6 DIM), and 8 in late lactation (283 +/-3.4 DIM). For cows in early, mid, and late lactation, milk yield was 34.4, 34.4, and 21.4 L/d [standard error of difference (SED) 1.78]; milk fat was 50.4, 40.3, and 41.4 g/L (3.68); milk citrate was 11.3, 9.7, and 10.1 mmol/L (0.64); the ratio of 4-14 C:18-20 C fatty acids was 0.9, 1.3, and 1.2 (0.07). Activity of the fatty acid synthase enzyme system (EC 2.3.1.85) was calculated as acetate used for chain elongation (ACE); ACE (mol/d) for cows in early, mid, and late lactation, was 7.3, 11.1, and 8.1 (SED 1.05). For individual cows, citrate (mmol/L) = 14.3 -0.44 xACE (r2 = 0.58). We propose that ACE provides a more accurate indication of synthase activity than do fatty acid ratios or yields. This study confirms the hypothesis that variation in milk citrate with stage of lactation is related to de novo synthesis of fatty acids and that the relationship is independent of diet and milk yield.

Acetates↗