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PubMed1991

Oxalate as a potent and selective inhibitor of spinach (Spinacia oleracea) leaf NADPH-dependent hydroxypyruvate reductase.

Purified spinach (Spinacia oleracea) NADPH-preferring hydroxypyruvate reductase (HPR-2) was potently and selectively inhibited by oxalate, an end product of metabolism in plants. Both hydroxypyruvate- and glyoxylate-dependent rates of the HPR-2 enzyme were affected. Oxalate acted as an uncompetitive inhibitor of the enzyme, with Ki values of 7 and 36 microM for the NADPH/hydroxypyruvate and NADPH/glyoxylate pairs of reactants respectively. Oxalate, at millimolar levels, caused less than 10% inhibition of purified spinach NADH-preferring HPR (HPR-1) and had no effect on purified spinach NADPH-preferring glyoxylate-specific reductase (GR-1). The inhibition of spinach HPR-2 by oxalate is by far the strongest for any known inhibitor of leaf HPR and GR activities. In photosynthetic tissues, oxalate could potentially act as a primary regulator of extraperoxisomal metabolism of hydroxypyruvate and glyoxylate.

Alcohol Oxidoreductases↗
PubMed2003

Influence of cranberry juice on the urinary risk factors for calcium oxalate kidney stone formation.

OBJECTIVE: To investigate the potential influence of cranberry juice on urinary biochemical and physicochemical risk factors associated with the formation of calcium oxalate kidney stones, as this product might affect the chemical composition of urine. SUBJECTS AND METHODS: Urinary variables were assessed in a randomized cross-over trial in 20 South African men (students) with no previous history of kidney stones. The first group of 10 subjects drank 500 mL of cranberry juice diluted with 1500 mL tap water for 2 weeks, while the second group drank 2000 mL of tap water for the same period. This was followed by a 2-week 'washout' period before the two groups crossed over. During the experimental phase subjects kept a 3-day food diary to assess their dietary and fluid intakes; 24-h urine samples were collected at baseline and on day 14 of the trial periods, and analysed using modern laboratory techniques. Urine analysis data were used to calculate the relative urinary supersaturations of calcium oxalate, uric acid and calcium phosphate. Data were assessed statistically by analysis of variance. RESULTS: The ingestion of cranberry juice significantly and uniquely altered three key urinary risk factors. Oxalate and phosphate excretion decreased while citrate excretion increased. In addition, there was a decrease in the relative supersaturation of calcium oxalate, which tended to be significantly lower than that induced by water alone. CONCLUSION: Cranberry juice has antilithogenic properties and, as such, deserves consideration as a conservative therapeutic protocol in managing calcium oxalate urolithiasis.

Beverages↗
PubMed2005

Structural and spectroscopic studies shed light on the mechanism of oxalate oxidase.

Oxalate oxidase (EC 1.2.3.4) catalyzes the conversion of oxalate and dioxygen to hydrogen peroxide and carbon dioxide. In this study, glycolate was used as a structural analogue of oxalate to investigate substrate binding in the crystalline enzyme. The observed monodentate binding of glycolate to the active site manganese ion of oxalate oxidase is consistent with a mechanism involving C-C bond cleavage driven by superoxide anion attack on a monodentate coordinated substrate. In this mechanism, the metal serves two functions: to organize the substrates (oxalate and dioxygen) and to transiently reduce dioxygen. The observed structure further implies important roles for specific active site residues (two asparagines and one glutamine) in correctly orientating the substrates and reaction intermediates for catalysis. Combined spectroscopic, biochemical, and structural analyses of mutants confirms the importance of the asparagine residues in organizing a functional active site complex.

Binding Sites↗
PubMedDate not supplied

Mode of action: oxalate crystal-induced renal tubule degeneration and glycolic acid-induced dysmorphogenesis--renal and developmental effects of ethylene glycol.

Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.

Abnormalities, Drug-Induced↗
PubMed2002

Oxalate, germins, and higher-plant pathogens.

Earlier surveys (1, B. G. Lane. [1991] FASEB J. 5, 2983-2901; 2, B. G. Lane. [1994] FASEB J. 8, 294-301) helped to uproot entrenched views of plant oxalate as a static substance. It is now recognized that oxalate oxidases (OXOs) found in the "true cereals" (barley, maize, oat, rice, rye, wheat), the so-called germin OXOs (G-OXOs), or simply germins, are involved in cereal defence responses to invasion by fungal pathogens and that they show promise of being valuable agents of plant defence in dicotyledons, where they are not found naturally. G-OXOs have very peculiar properties: (a) their water-soluble oligomeric structures and enzymic activity are stable during SDS-PAGE and nitrocellulose blotting, (b) their undenatured water-soluble forms are refractory to the action of broad-specificity proteases, (c) their water-insoluble forms occur abundantly (approximately 50%) in the extracellular matrix (cell walls) of wheat, and probably in varying amounts in the cell walls of other true cereals. Transfer of the wheat G-OXO coding element to dicotyledons has been found, in all cases so far examined, to result in improved resistance to fungal pathogens. The possible nature of the improved resistance is discussed in relation to (a) generation of microcidal concentrations of hydrogen peroxide when the G-OXOs act on oxalate, (b) elicitation of hypersensitive cell death at lower concentrations of hydrogen peroxide, (c) formation of effective barriers against predator penetration by the hydrogen-peroxide-mediated lignification of cell walls, and (d) destruction of oxalate, which is an inhibitor of the hypersensitive response, a strategy of particular importance in the case of ubiquitous predator organisms such as Sclerotinia sclerotiorum, which secrete high concentrations of oxalate as a toxin.

Fungi↗
PubMed1977

Hyperoxaluria and calcium oxalate nephrolithiasis after jejunoileal bypass.

Patients with ileal disease, ileal resection, and jejunoileal bypass are at increased risk of forming calcium oxalate renal calculi because of enhanced absorption of dietary oxalate. Intraluminal solubility of oxalate is an important determinant for hyperabsorption and may be regulated by intraluminal concentration of calcium and fatty acids. Malabsorbed bile salts and fatty acids may alter intestinal permeability, leading to increased passive diffusion of oxalate. Management includes a diet low in oxalate and fat content, dietary calcium of 750 mg/day, and cholestyramine.

Bile Acids and Salts↗
PubMed1989

Oxalate: effect on calcium absorbability.

Absorption of calcium from intrinsically labeled Ca oxalate was measured in 18 normal women and compared with absorption of Ca from milk in these same subjects, both when the test substances were ingested in separate meals and when ingested together. Fractional Ca absorption from oxalate averaged 0.100 +/- 0.043 when ingested alone and 0.140 +/- 0.063 when ingested together with milk. Absorption was, as expected, substantially lower than absorption from milk (0.358 +/- 0.113). Nevertheless Ca oxalate absorbability in these women was higher than we had previously found for spinach Ca. When milk and Ca oxalate were ingested together, there was no interference of oxalate in milk Ca absorption and no evidence of tracer exchange between the two labeled Ca species.

Adult↗
PubMed1981

Identification of atypical calcium oxalate crystalluria following ethylene glycol ingestion.

A case of ethylene glycol poisoning was associated with heavy crystalluria unidentifiable by light microscopy. Extensive analysis utilizing scanning electron microscopy, x-ray fluorescence, and diffraction method revealed that the sediment contained calcium oxalate monohydrate in one crystallographic phase. Newest diffraction data for identification of the various forms of calcium oxalate, along with the photographs of the crystals by light and electron microscopy, are included. Fifty cases of ethylene glycol poisoning were reviewed to ascertain the most common form of calcium oxalate crystalluria. The search revealed scanty morphologic data associated with the calcium oxalate crystalluria; however, numerous forms were reported. It is concluded that calcium oxalate crystalluria following ethylene glycol ingestion may assume many forms, which should be recognized to facilitate the rapid diagnosis of ethylene glycol ingestion.

Adult↗
PubMed2005

Oxalic acid as a fungal acaracidal virulence factor.

Cell-free culture supernatants of the entomopathogenic fungus Beauveria bassiana (Bals.) Vuillemin were able to induce mortality in several tick species, including adult Ambylomma americanum (L.), Ambylomma maculatum Koch, and Ixodes scapularis Say. Four lines of experimental evidence support the hypothesis that oxalic acid secretion by B. bassiana, coupled to a reduction in the pH of the medium, act as potent acaricidal factors during pathogenesis. 1) Acaracidal activity of culture supernatants was retained after treatments including boiling and protease digestion, but was lost after dialysis. 2) Metabolite analyses indicated oxalate to be the major secreted organic compound present in the active culture supernatants. 3) Treatment of ticks with the pure compound oxalate at pH 4.0 resulted in almost 80% mortality in adult A. americanum ticks within 14 d, whereas treatment of ticks with oxalate at pH 7.0, or with formate, citrate, or phosphate at both pH 4 and 7 resulted in <10% mortality, even after 28 d. 4) Cell-free culture supernatants from B. bassiana mutants with decreased oxalate production displayed lower acaricide activity than wild type.

Animals↗
PubMed2004

The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis.

BACKGROUND: Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship. METHODS: The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (AP(CaOx)) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants. RESULTS: Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91+/-0.89 vs 3.46+/-1.39 mmol/24 h, P = 0.004) and higher AP(CaOx) (2.02+/-0.51 vs 1.53+/-0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and AP(CaOx) between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7+/-12.1 vs 38.1+/-12.7 years, P = 0.008) and higher values of FHS (2.45+/-1.9 vs 0.83+/-0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative. CONCLUSIONS: Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.

Adult↗
PubMed2004

Calcium oxalate monohydrate, a metabolite of ethylene glycol, is toxic for rat renal mitochondrial function.

Ethylene glycol poisoning can produce acute renal failure, requiring long-term hemodialysis to restore function. The mechanism of the renal failure is unknown, but is associated with tubular cell necrosis and ethylene glycol metabolism. The end metabolite of ethylene glycol is oxalic acid, the precipitation of which as calcium oxalate monohydrate (COM) crystals in the tubular lumen has been linked with the renal toxicity. Our recent studies suggest that COM is an intracellular toxicant to normal human proximal tubule cells in culture. The present studies were designed to assess whether COM or ionic oxalate alters mitochondrial function so as to lead to renal cell death. In isolated rat kidney mitochondria, COM produced a dose-dependent decrease in State 3 respiration (40% decrease at 0.05 mM COM with either succinate or glutamate/malate as substrate), without affecting either State 4 respiration or the ADP/O ratio. COM, from 0.01-0.05 mM also dose-dependently increased mitochondrial swelling, which was completely blocked by cyclosporin A. The inhibition of State 3 respiration, however, was not reversed by cyclosporin A administration. Potassium oxalate, at concentrations up to 5 mM did not inhibit mitochondrial respiration or induce swelling. These results suggest that COM, and not the oxalate ion, damages rat kidney mitochondria and induces the mitochondrial permeability transition, which may then lead to renal cell death. Since COM is transported intracellularly by kidney cells, the renal toxicity of ethylene glycol may result from inhibition of mitochondrial respiratory function in proximal tubular cells by COM crystals.

Animals↗
PubMed1990

Calcium oxalate crystals in breast biopsies. The missing microcalcifications.

Most calcifications detected by mammography and specimen radiography are readily identified by histologic sections stained with hematoxylin and eosin (H&E) or the von Kossa stain. However, calcifications composed of calcium oxalate crystals are not always seen in sections stained with H&E or with von Kossa. To study the incidence of calcium oxalate crystals in breast biopsies, we used polarized light microscopy to review 153 needle-localization breast biopsies. Birefringent crystals were observed in 19 cases (17 benign and 2 malignant), but typical calcium phosphate microcalcifications were revealed by H&E in only 16 of these 19 cases. Multiple H&E sections through the blocks of the remaining three cases did not reveal typical microcalcifications. These crystals did stain with silver nitrate/rubeanic acid with 5% acetic acid pretreatment but failed to stain with von Kossa and alizarin red at pH 4.2. This suggested that they were composed of calcium oxalate. Analytical electron microscopy performed in one of the three cases without typical microcalcifications demonstrated only a calcium peak of energy-dispersive x-ray analysis and an electron-diffraction pattern compatible with calcium oxalate monohydrate. We conclude that discrepancies between the amount of microcalcifications seen on the mammogram or on the x-ray film of the specimen or the paraffin blocks and the amount of microcalcifications seen on the H&E slides may be explained by the presence of calcium oxalate crystals. These crystals are detected with specimen radiography but are not easily seen on H&E slides unless polarized light microscopy is used. Polarized light microscopy and silver nitrate/rubeanic acid with 5% acetic acid pretreatment should be used for breast biopsy specimens when typical microcalcifications are not seen on H&E-stained sections.

Biopsy, Needle↗
PubMed1997

The effects of (L)-2-oxothiazolidine-4-carboxylate on urinary oxalate excretion.

PURPOSE: A phase I study was done to evaluate the safety and pharmacokinetics of (L)-2-oxothiazolidine-4-carboxylate (OTZ). An ancillary objective was to compare the effects of treatment with 2 levels of OTZ to placebo on urinary oxalate excretion in healthy male subjects. MATERIALS AND METHODS: Individuals underwent intravenous infusion of 70 (6) or 100 (6) mg/kg, body weight OTZ, or placebo for 2 hours at 4, 8-hour intervals. Urine was collected during the 12 hours before treatment, and at 0 to 4, 4 to 8, 8 to 24, 24 to 28, 28 to 32 and 32 to 48 hours after the initial infusion. Urine samples were assayed for creatinine, oxalate, citrate, sulfate, urate, phosphate and pH. RESULTS: Urinary oxalate excretion relative to creatinine decreased significantly in the 100 mg./kg. dose group by 4.1 mg./gm. during the first 24 hours and by 4.6 mg./gm. in 24 to 48 hours compared to baseline values (p < 0.05). Slight decreases of 0.9 and 1.1 mg./gm., respectively, in the 70 mg./kg. dose group, and 1.6 and 2.3 mg./gm., respectively, in the placebo group were observed. Oxalate excretion on day 2 in the 100 mg./kg. dose group was significantly less than that in the placebo group (p = 0.04). Urinary pH decreased and sulfate excretion increased with OTZ therapy. CONCLUSIONS: Treatment with 100 mg./kg. OTZ every 8 hours decreases urinary oxalate excretion in healthy men.

Adult↗
PubMed2004

Effect of angiotensin II receptor blockage on osteopontin expression and calcium oxalate crystal deposition in rat kidneys.

Hyperoxaluria leads to calcium oxalate (CaOx) crystallization and development of tubulointerstitial lesions in the kidneys. Treatment of hyperoxaluric rats with angiotensin II (Ang II) type I receptor blocker (ARB) reduces lesion formation. Because Ang II mediates osteopontin (OPN) synthesis, which is involved in both macrophage recruitment and CaOx crystallization, it was hypothesized that ARB acts via OPN. Hyperoxaluria was induced in 10-wk-old male Sprague-Dawley rats, and they were treated with ARB candesartan. At the end of 4 wk, kidneys were examined for crystal deposits, ED-1-positive cells, and expression of OPN mRNA. PCR was used to quantify OPN, renin, and angiotensin-converting enzyme (ACE) mRNA in kidneys. RIA was used to determine renal, plasma, and urinary OPN; plasma renin; Ang II and ACE; and renal Ang II. For evaluating oxidative stress, malondialdehyde was measured. Urinary calcium, oxalate, creatinine, and albumin were also determined. Despite similar urinary calcium and oxalate levels, kidneys of hyperoxaluric rats on candesartan had fewer CaOx crystals, fewer ED-1-positive cells, reduced OPN expression, and reduced malondialdehyde than hyperoxaluric rats. Urinary albumin excretion and serum creatinine levels improved significantly on candesartan treatment. mRNA for OPN, renin, and ACE were significantly elevated in hyperoxaluric rats. OPN synthesis and production increased with hyperoxaluria but to a lesser extent in candesartan-treated hyperoxaluric rats. These results show for the first time that oxalate can activate the renal renin-angiotensin system and that oxalate-induced upregulation of OPN is in part mediated via renal renin-angiotensin system.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

Thiazide does not affect urine oxalate excretion.

PURPOSE: We assessed the effects of thiazide treatment on urine oxalate excretion in patients with kidney stones. MATERIALS AND METHODS: Of 537 patients (231 women), 209 (81 women) received thiazide for stone prevention. Urine oxalate was measured in 3, 24-hour urines before treatment, and in 1, 24-hour urine after 6 to 12 weeks of treatment. This was an observational cohort and treatment was not randomized. RESULTS: Urine oxalate increased in general. There was no difference in increase with or without thiazide, whether one considered simple t test comparisons or used ANOVA with pretreatment oxalate excretion as a covariate. CONCLUSIONS: Thiazide administration exerts no measurable effect on urine oxalate excretion that can be detected in clinical practice.

Adult↗
PubMed2004

Minipump induced hyperoxaluria and crystal deposition in rats: a model for calcium oxalate urolithiasis.

PURPOSE: Unraveling the mechanisms leading to clinically active calcium oxalate (CaOx) stone disease and the development of effective medical therapies to treat it have been hampered by the lack of appropriate animal models. To address this problem we developed a model of hyperoxaluria and calcium oxalate crystal deposition by implanting osmotic minipumps subcutaneously into male rats, that is minipump induced hyperoxaluria and crystal deposition in rats. MATERIALS AND METHODS: Male Harlan-Sprague Dawley rats (225 to 290 gm) were implanted subcutaneously with 1-week 2 ml osmotic minipumps containing 1.5 M potassium oxalate (360 microM KOx/24 hours, [KOx-trt], 11) or phosphate buffered saline (PBS-trt, 9) on days 1 and 7. The 24-hour urine collections were performed on days 0, 4, 7, 11 and 14. Data were analyzed by ANOVA and Tukey's HSD. Urinary crystals were analyzed by light microscopy. Kidneys were harvested on day 14 and processed for light and polarizing microscopy, and RNA analysis.RESULTS Mean overall creatinine excretion +/- SEM (PBS-trt 107 +/- 7 and KOx-trt 123 +/- 6 microM/24 hours, p >0.07) and day 14 serum creatinine (PBS-trt 83 +/- 4 and KOx-trt 83 +/- 5 microM, p >or=0.9) were similar in the 2 treatment groups. Overall urinary volume (PBS-trt 11.3 +/- 0.8 and KOx-trt 18.0 +/- 1.5 ml/24 hours, p <or=0.001) and oxalate (OX) excretion (PBS-trt 9.2 +/- 0.6 and KOx-trt 44 +/- 4.2 microM/24 hours, p <or=0.001) were higher in KOx-trt vs PBS-trt rats. In KOx-trt rats OX excretion on day 0 was significantly less than on any day after implantation (p <or=0.01). All KOx-trt rats excreted calcium oxalate dihydrate crystals by day 4 and had intrarenal deposits of birefringent crystals by day 14. Overall the morphology of kidneys of OX rats was normal, although localized regions of inflammation and tubular debris were occasionally observed. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that the expression of 3 distress molecules tumor necrosis factor receptor, osteopontin and kidney injury molecule were up-regulated in KOx-trt kidneys. CONCLUSIONS: The model of minipump induced hyperoxaluria and crystal deposition in rats reliably induces hyperoxaluria, CaOx crystalluria and CaOx crystal deposition. These characteristics make it an appropriate model for investigations of the effects of OX on renal physiology as well as investigating the efficacy of new therapeutics.

Animals↗
PubMed2003

Isolation of a crystal matrix protein associated with calcium oxalate precipitation in vacuoles of specialized cells.

The formation of calcium (Ca) oxalate crystals is considered to be a high-capacity mechanism for regulating Ca in many plants. Ca oxalate precipitation is not a stochastic process, suggesting the involvement of specific biochemical and cellular mechanisms. Microautoradiography of water lettuce (Pistia stratiotes) tissue exposed to 3H-glutamate showed incorporation into developing crystals, indicating potential acidic proteins associated with the crystals. Dissolution of crystals leaves behind a crystal-shaped matrix "ghost" that is capable of precipitation of Ca oxalate in the original crystal morphology. To assess whether this matrix has a protein component, purified crystals were isolated and analyzed for internal protein. Polyacrylamide gel electrophoresis revealed the presence of one major polypeptide of about 55 kD and two minor species of 60 and 63 kD. Amino acid analysis indicates the matrix protein is relatively high in acidic amino acids, a feature consistent with its solubility in formic acid but not at neutral pH. 45Ca-binding assays demonstrated the matrix protein has a strong affinity for Ca. Immunocytochemical localization using antibody raised to the isolated protein showed that the matrix protein is specific to crystal-forming cells. Within the vacuole, the surface and internal structures of two morphologically distinct Ca oxalate crystals, raphide and druse, were labeled by the antimatrix protein serum, as were the surfaces of isolated crystals. These results demonstrate that a specific Ca-binding protein exists as an integral component of Ca oxalate crystals, which holds important implications with respect to regulation of crystal formation.

Amino Acids↗
PubMed2000

Isolation of Medicago truncatula mutants defective in calcium oxalate crystal formation.

Plants accumulate crystals of calcium oxalate in a variety of shapes, sizes, amounts, and spatial locations. How and why many plants form crystals of calcium oxalate remain largely unknown. To gain insight into the regulatory mechanisms of crystal formation and function, we have initiated a mutant screen to identify the genetic determinants. Leaves from a chemically mutagenized Medicago truncatula population were visually screened for alterations in calcium oxalate crystal formation. Seven different classes of calcium oxalate defective mutants were identified that exhibited alterations in crystal nucleation, morphology, distribution and/or amount. Genetic analysis suggested that crystal formation is a complex process involving more than seven loci. Phenotypic analysis of a mutant that lacks crystals, cod 5, did not reveal any difference in plant growth and development compared with controls. This finding brings into question the hypothesized roles of calcium oxalate formation in supporting tissue structure and in regulating excess tissue calcium.

Calcium↗