Uric acid changes in urine and plasma: An effective tool in screening for purine inborn errors of metabolism and other pathological conditions

Simoni, Ruth E.; Gomes, Luiz Nelson Lopes Ferreira; Scalco, Fernanda B.; Oliveira, Cesário Paulo Honório de; Neto, Francisco Radler de Aquino; Oliveira, Maria Lúcia Costa de

doi:10.1007/s10545-007-0455-8

Cited by 37 publications

(19 citation statements)

References 47 publications

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“…No such change was exhibited in the urine of mice receiving 3 Gy, indicating that certain markers have the potential to be used for radiation dosimetry. Uric acid is the final product of the purine metabolism in humans and is synthesized in the liver, therefore indicating that radiationinduced excretion may be due to increased purine synthesis or direct failure of purine recycling, which leads to nucleotide depletion (48). As the most effective free radical scavenger, uric acid is decreased in the plasma of radiotherapy patients, probably as a result of oxidative stress (49).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Mouse Urinary Metabolic Profiles after Exposure to the Inflammatory Stressors γ Radiation and Lipopolysaccharide

2012

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Metabolomics on easily accessible biofluids has the potential to provide rapid identification and distinction between stressors and inflammatory states. In the event of a radiological event, individuals with underlying medical conditions could present with similar symptoms to radiation poisoning, prominently nausea, diarrhea, vomiting and fever. Metabolomics of radiation exposure in mice has provided valuable biomarkers, and in this study we aimed to identify biomarkers of lipopolysaccharide (LPS) exposure to compare and contrast with ionizing radiation. LPS treatment leads to a severe inflammatory response and a cytokine storm, events similar to radiation exposure, and LPS exposure can recapitulate many of the responses seen in sepsis. Urine from control mice, LPS-treated mice, and mice irradiated with 3, 8 and 15 Gy of γ rays was analyzed by LCMS, and markers were extracted using SIMCA-P+ and Random Forests. Markers were validated through tandem mass spectrometry against pure chemicals. Five metabolites, cytosine, cortisol, adenine, O-propanoylcarnitine and isethionic acid, showed increased excretion at 24 h after LPS treatment (P < 0.0001, 0.0393, 0.0393, <0.0001 and 0.0004, respectively). Of these, cytosine, adenine and O-propanoylcarnitine showed specificity to LPS treatment when compared to radiation. On the other hand, increased excretion of cortisol after LPS and radiation treatments indicated a rapid systemic response to inflammatory agents. Isethionic acid excretion, however, showed elevated levels not only after LPS treatment but also after a very high dose of radiation (15 Gy), while additional metabolites showed responsiveness to radiation but not LPS. Metabolomics therefore has the potential to distinguish between different inflammatory responses based on differential ion signatures. It can also provide quick and reliable assessment of medical conditions in a mass casualty radiological scenario and aid in effective triaging.

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Section: Discussionmentioning

confidence: 99%

Comparison of Mouse Urinary Metabolic Profiles after Exposure to the Inflammatory Stressors γ Radiation and Lipopolysaccharide

2012

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“…Moreover, metabolomic analysis can also be utilized to identify biomarkers of drug treatment (23). From a therapeutic point of view, it is well accepted that MTX is effective in only 60-75% of RA patients (24).…”

Section: Discussionmentioning

confidence: 99%

“…It appeared that nucleic acid metabolism may be highly interrelated to the therapeutic effects, with uric acid and uracil being two of the most prominent metabolites noted. In addition, the changes in levels of TMAO and hypoxanthine suggest an alteration in purine and pyrimidine ratios, and in turn may affect cell metabolism, energy conservation and biosynthetic pathways, even signal transduction and translation (23). Glycine has been suggested to have anti-inflammatory properties by acting on macrophage chloride channels to blunt cytokine release, and methionine is associated with SAM synthesis that may influence metabolism of nucleic acid (24,25).…”

Section: Discussionmentioning

confidence: 99%

1H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis

Wang

Chen

Yang

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. To identify the major serum biomarkers predicting the response to methotrexate (MTX) treatment in patients with early rheumatoid arthritis (RA), we evaluated the relationships between the individual response to MTX and various associated factors utilizing the 1 H nuclear magnetic resonance ( 1 H NMR)-based metabolomic method. Thirty-eight early RA patients were enrolled in this cohort study, and they received MTX (10 mg/week) orally as monotherapy for 24 weeks. According to the American College of Rheumatology criteria for improvement, clinical evaluation following MTX treatment was carried out at baseline and at the end of 24 weeks. Furthermore, collected serum samples were analyzed using 600 M 1 H NMR for spectral binning. The obtained data were processed by both the unsupervised principal component analysis (PCA) and the supervised partial least squares discriminant analysis (PLS-DA). Lastly, multivariate analyses were performed to recognize the spectral pattern of endogenous metabolites related to MTX treatment. Differential clustering of 1 H NMR spectra identified by PCA was found between the effective (n=25) and non-effective (n=13) group of RA patients receiving MTX treatment. Multivariate statistical analysis showed a difference in metabolic profiles between the two groups using PLS-DA (R 2 =0.802, Q 2 =0.643). In targeted profiling, 11 endogenous metabolites of the effective group showed a significant difference when compared with those of the non-effective group (p<0.05). Serum metabolites correlated with MTX treatment in patients with early RA were identified, which may be the major predictive factors for evaluating the response to MTX treatment in patients with early RA. Furthermore, our results highlight the usefulness of 1 H NMR-based metabolomics as a feasible and efficient prognostic tool for predicting therapeutic efficacy to MTX treatment. IntroductionRheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, which is characterized by persistent synovitis, systemic inflammation and autoantibodies (1). Methotrexate (MTX) is the most widely used and is regarded as the anchor drug in the treatment of RA. Despite the advent of newer biologic therapies, MTX retains its central role since it is relatively inexpensive, broad experience with its use exists, and it is widely used in combination regimens with other disease-modifying antirheumatic drugs (DMARDs) (2). In the US and European countries, the recommended general dose of MTX is 15-20 mg/week, but individual optimal dose is in the range of 5-25 mg/week. In China, the conventional dose of MTX is 10 mg/week, but in practice 5-20 mg/week is prescribed based on individual sensitivity to and tolerance of MTX (3,4). Although well proven, it is recognized that there are large individual differences in the optimal dose of MTX for RA patients (5). The reasons for those individual differences are thought to be different concentrations of intracellular MTX-polyglutamates (MTX-PGs) and different enzyme activities at MTX-active sit...

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“…Therefore, measurement of uric acid in plasma and urine may lead to an indication for several, but not all, purine defects (Simoni et al 2007).…”

Section: Significance Of Uric Acidmentioning

confidence: 99%

Inborn errors of purine and pyrimidine metabolism

Jurecka

2009

J of Inher Metab Disea

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Genetic disorders of purine and pyrimidine (PP) metabolism are under-reported and infrequently mentioned in the general literature, as well as in reviews dedicated to other inborn errors of metabolism. Owing to limited awareness, relatively recent recognition, as well as considerable phenotypic variation, these disorders may often be misdiagnosed or remain undiagnosed. Disorders that arise as a result of dysfunction in PP metabolism represent some of the most challenging diagnostic problems in medicine. In addition to their low prevalence rates, they also present with extremely variable signs and symptoms. They may affect any system in a variety of manners, and often mimic other, more recognizable disorders. The diagnostic problem is compounded by the fact that some biochemically affected patients are symptom-free. Rapidly evolving laboratory techniques such as high-performance liquid chromatography coupled to tandem mass spectrometry are now well established as the preferred method for detection for these defects, but currently the most important step in diagnosis consists of suspecting the disorder. Diagnosis is vital because genetic counselling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. If undiagnosed, these disorders can be devastating to patients and their families, resulting in early death or institutionalization for the rest of patient's life. This article describes the current state of knowledge about inborn errors of purine and pyrimidine metabolism, focusing on the varying clinical presentations, the laboratory findings and discusses indications for selective screening for these disorders.

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Uric acid changes in urine and plasma: An effective tool in screening for purine inborn errors of metabolism and other pathological conditions

Cited by 37 publications

References 47 publications

Comparison of Mouse Urinary Metabolic Profiles after Exposure to the Inflammatory Stressors γ Radiation and Lipopolysaccharide

Comparison of Mouse Urinary Metabolic Profiles after Exposure to the Inflammatory Stressors γ Radiation and Lipopolysaccharide

1H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis

Inborn errors of purine and pyrimidine metabolism

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