Disease relevance of citric acid

• 4-Dimethylaminoazobenzene was fed to Wistar-derived, male, albino rats after hepatic siderosis had been induced by including ferric citrate in the diet [1].
• Signal transfer through three compartments: transcription initiation of the Escherichia coli ferric citrate transport system from the cell surface [2].
• In addition, outer membrane receptors together with the TonB--ExbB--ExbD complex are directly involved in induction of the transcription of ferric citrate and pseudobactin transport genes of Escherichia coli and Pseudomonas putida, respectively [3].
• Ferric nitrilotriacetate (Fe-NTA) and ferric citrate (Fe-citrate) were used to study the cellular damage mediated by iron overload with respect to cytotoxicity, lipid peroxidation, DNA strand breaks and sister chromatid exchanges (SCE) [4].
• A 63.9 kDa periplasmic tetrahaem flavocytochrome c(3), designated Ifc(3), was found to be expressed in Shewanella frigidimarina NCIMB400 grown anaerobically with ferric citrate or ferric pyrophosphate as the sole terminal electron acceptor, but not in anaerobic cultures of the bacterium with other respiratory substrates [5].

High impact information on citric acid

• The uptake of ferric citrate into the periplasmic space of fecA and tonB mutants via diffusion through the porin channels did not induce transcription of fec transport genes [2].
• Here we demonstrate that ferric citrate uptake into the periplasmic space between the outer and the cytoplasmic membranes is not required for fec gene induction [2].
• Point mutants in FecA displayed the constitutive expression of fec transport genes in the absence of ferric citrate but still required TonB, with the exception of one FecA mutant which showed a TonB-independent induction [2].
• Rather, FecA and the TonB, ExbB and ExbD proteins are involved in induction of the fec transport genes independent of their role in ferric citrate transport across the outer membrane [2].
• Functional analyses of these positions confirm their involvement in the mechanism that regulates transcriptional activation in response to ferric citrate binding at the cell surface [6].

Chemical compound and disease context of citric acid

• The uptake of iron supplied as ferric citrate or ferric parabactin was examined in aerobically grown whole cells and vesicles of Rhodopseudomonas sphaeroides [7].
• Iron uptake studies in Bifidobacterium bifidum var. pennsylvanicus were carried out using ferric citrate at iron concentrations above 0.01 mM and pH 7, ferrous iron at concentrations less than 0.01 mM at pH 5 [8].

Biological context of citric acid

• Carbon tetrachloride-induced and ferric citrate-induced lipid peroxidation were also accentuated in microsomes from ethanol-fed rats, by 76% and 108%, respectively [9].
• Ferric citrate (10(-3) M) inhibited both adherent and nonadherent NK cell activity, but had no effect upon ADCC [10].
• In rats with normal renal function (average creatinine clearance, 4.0 ml/min per kg), the average net intestinal absorption of phosphate over all balance periods was 103.3 mg/d for the control group versus 84.7 mg/d for the ferric citrate group (P < 0.005) [11].
• Cell proliferation was stimulated by the addition of human transferrin or ammonium ferric citrate to the medium [12].
• The shr mutant demonstrated reduced hemoglobin binding, though cell growth in iron-depleted medium supplemented with hemoglobin, whole blood, or ferric citrate was not affected, suggesting additional systems are involved in hemoglobin utilization [13].

Anatomical context of citric acid

• Transport of ferric citrate into cells of Escherichia coli K-12 involves two energy-coupled transport systems, one across the outer membrane and one across the cytoplasmic membrane [2].
• The inducer, ferric citrate, binds to an outer membrane transport protein, and without further transport elicits a signal that is transmitted across the outer membrane, the periplasm, and the cytoplasmic membrane into the cytoplasm [14].
• Ferrous ion chelators, bathophenanthroline disulfonate, and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types [15].
• Reconstitution of the H(+)-ATPase into liposomes was performed by sonicating a lipid mixture, with a composition similar to the reticulocyte plasma membrane, in a buffer containing ferric citrate [16].
• Additionally, cSHMT expression was not altered when HCF expression was induced in MCF-7 cells cultured with supplemental ferric citrate [17].

Associations of citric acid with other chemical compounds

• In hemin-restricted media, transferrin binding occurred despite addition of up to 10 mM ferric nitrate, ferric citrate, or ferric PPi, whereas addition of 10 micrograms of hemoglobin ml-1 repressed expression [18].
• However, ferric citrate and ferric nitrilotriacetate stimulated in a dose-dependent manner the growth of L. pneumophila in resident macrophages [19].
• Tissue distributions of i.v.-injected Ga-67 citrate and [59Fe] ferric citrate were measured in normal mice and in lymphoid-tumor hosts [20].
• Exposure of LLC-PK1 cells to 10(-4) M ferric citrate for 72 hours significantly decreased expression of the beta 1 integrin subunit as determined by flow cytometry [21].
• The renal tumor incidence and number of tumor nodules in hamsters treated with estradiol plus a diet enriched with iron (384 p.p.m. Fe as ferric citrate) for 5 months were 2- and 4-fold higher, respectively, than those observed in animals on an iron-poor diet plus estradiol (3.9 p.p.m. Fe, as ferric citrate) [22].

Gene context of citric acid

• Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P <.001; mean +/- SEM; n = 7) [15].
• Mobility band shift of fecA promoter DNA caused by cell lysates required growth of cells in the presence of ferric citrate and expression of FecA, FecI and FecR [23].
• 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 [24].
• A mutation of FTR1 did not impair the use of these siderophores but did affect the uptake of ferrioxamines E and B, as well as of ferric citrate, indicating that their utilization was independent of Sit1p [25].
• We conclude that transcription of the fec transport genes is regulated by FecI, which responds to ferric citrate via FecR. fecI and fecR co-transcription is inhibited by the iron-loaded Fur repressor, which then results in a low level of transcription of the fec transport genes [26].

Analytical, diagnostic and therapeutic context of citric acid

• We observed a consistent sequence of activation changes in rat knee synovia following a single intravenous injection of sterile ferric citrate at a dosage sufficient to cause a transient saturation of transferrin [27].
• Results of real-time PCR showed that A. actinomycetemcomitans JP2-12 exhibited significantly reduced expression of afuA (eightfold), fecBCDE (10-fold), and ftnAB (>50-fold), which encode a periplasmic ferric transport protein, a putative ferric citrate transporter, and ferritin, respectively [28].
• In contrast, supplementation of the fish oil diets with ferric citrate, significantly (P less than 0.05) increased tumor lipid peroxidation product levels and decreased tumor volume [29].
• Iron reductase activities for two substrates, ferripyochelin and ferric citrate, appear to be separate enzymes because of differences in heat stabilities, in locations in fractions of cell-free extracts, in reductant specificity, and in apparent sizes during gel filtration chromatography [30].
• An open-label, crossover study of a new phosphate-binding agent in haemodialysis patients: ferric citrate [31].

References