- Reversal of an unfavorable effect of hydrochlorothiazide compared to angiotensin converting enzyme inhibitor on serum uric acid and oxypurine levels by estrogen-progestin therapy in hypertensive postmenopausal women. [Journal Article]
- CMCurr Med Res Opin 2019 Jun 17; :1-11
- CONCLUSIONS: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.
- Metabolic interaction between purine nucleotide cycle and oxypurine cycle during skeletal muscle contraction of different intensities: a biochemical reappraisal. [Review]
- MMetabolomics 2018 02 27; 14(4):42
- A substrate cycle is a metabolic transformation in which a substrate A is phosphorylated to A-P at the expense of ATP (or another "high energy" compound), and A-P is converted back to A by a nucleoti…
A substrate cycle is a metabolic transformation in which a substrate A is phosphorylated to A-P at the expense of ATP (or another "high energy" compound), and A-P is converted back to A by a nucleotidase or a phosphatase. Many biochemists resisted the idea of such an ATP waste. Why a non-phosphorylated metabolite should be converted into a phosphorylated form, and converted back to its non-phosphorylated form through a "futile cycle"?
- Inhibiting PNP for the therapy of hyperuricemia in Lesch-Nyhan disease: Preliminary in vitro studies with analogues of immucillin-G. [Journal Article]
- JIJ Inherit Metab Dis 2019; 42(1):178-185
- Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation,…
Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo- and d-ribo-nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin-G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.
- Adenosine 5'-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection. [Review]
- MMetabolites 2018 May 02; 8(2)
- The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular system, which may be used for management of hy…
The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular system, which may be used for management of hypertension and cardiometabolic diseases. In response to ischemia and cardiovascular injury, ATP is broken down to release adenosine. The effect of adenosine is very short lived because it is rapidly taken up by erythrocytes (RBCs), myocardial and endothelial cells, and also rapidly catabolized to oxypurine metabolites. Intracellular adenosine is phosphorylated back to adenine nucleotides via a salvage pathway. Extracellular and intracellular ATP is broken down rapidly to ADP and AMP, and finally to adenosine by 5′-nucleotidase. These metabolic events are known to occur in the myocardium, endothelium as well as in RBCs. Exercise has been shown to increase metabolism of ATP in RBCs, which may be an important mechanism for post-exercise hypotension and cardiovascular protection. The post-exercise effect was greater in hypertensive than in normotensive rats. The review summarizes current evidence in support of ATP metabolism in the RBC as a potential surrogate biomarker for cardiovascular protection and toxicities. It also discusses the opportunities, challenges, and obstacles of exploiting ATP metabolism in RBCs as a target for drug development and precision medicine.
- Effect of Cardiovascular Injury on Catabolism of Adenosine and Adenosine 5-'Triphosphate in Systemic Blood in a Freely Moving Rat Model In Vivo. [Journal Article]
- DMDrug Metab Lett 2016; 10(3):219-226
- CONCLUSIONS: Cardiovascular injury induced by isoproterenol resulted in breakdown of ATP to ADP and AMP in the RBC and also breakdown of ADO to UA in plasma and other tissues.
- Hypoxanthine Intrastriatal Administration Alters Neuroinflammatory Profile and Redox Status in Striatum of Infant and Young Adult Rats. [Journal Article]
- MNMol Neurobiol 2017; 54(4):2790-2800
- Hypoxanthine, the major oxypurine metabolite involved in purine's salvage pathway in the brain, is accumulated in Lesch-Nyhan disease, an inborn error of metabolism of purine. The purpose of this stu…
Hypoxanthine, the major oxypurine metabolite involved in purine's salvage pathway in the brain, is accumulated in Lesch-Nyhan disease, an inborn error of metabolism of purine. The purpose of this study was to investigate the effects of hypoxanthine intrastriatal administration on infant and young adult rats submitted to stereotactic surgery. We analyzed the effect of hypoxanthine on neuroinflammatory parameters, such as cytokine levels, immunocontent of NF-κB/p65 subunit, iNOS immunocontent, nitrite levels, as well as IBA1 and GFAP immunocontent in striatum of infant and young adult rats. We also evaluate some oxidative parameters, including reactive species production, superoxide dismutase, catalase, glutathione peroxidase activities, as well as DNA damage. Wistar rats of 21 and 60 days of life underwent stereotactic surgery and were divided into two groups: control (infusion of saline 0.9 %) and hypoxanthine (10 μM). Intrastriatal administration of hypoxanthine increased IL-6 levels in striatum of both ages of rats tested, while TNF-α increased only in 21-day-old rats. Hypoxanthine also increased nuclear immunocontent of NF-κB/p65 subunit in striatum of both ages of rats. Nitrite levels were decreased in striatum of 21-day-old rats; however, the immunocontent of iNOS was increased in striatum of hypoxanthine groups. Microglial and astrocyte activation was seen by the increase in IBA1 and GFAP immunocontent, respectively, in striatum of infant rats. All oxidative parameters were altered, suggesting a strong neurotoxic hypoxanthine role on oxidative stress. According to our results, hypoxanthine intrastriatal administration increases neuroinflammatory parameters perhaps through oxidative misbalance, suggesting that this process may be involved, at least in part, to neurological disorders found in patients with Lesch-Nyhan disease.
- DNA damage in cells exhibiting radiation-induced genomic instability. [Journal Article]
- MMutagenesis 2015; 30(3):451-8
- Cells exhibiting radiation-induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetu…
Cells exhibiting radiation-induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesis that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.
- Uridine--an indicator of post-exercise uric acid concentration and blood pressure. [Journal Article]
- PRPhysiol Res 2015; 64(4):467-77
- Studies have shown that uridine concentration in plasma may be an indicator of uric acid production in patients with gout. It has been also postulated that uridine takes part in blood pressure regula…
Studies have shown that uridine concentration in plasma may be an indicator of uric acid production in patients with gout. It has been also postulated that uridine takes part in blood pressure regulation. Since physical exercise is an effective tool in treatment and prevention of cardio-vascular diseases that are often accompanied by hyperuricemia and hypertension, it seemed advisable to attempt to evaluate the relationship between oxypurine concentrations (Hyp, Xan and UA) and that of Urd and BP after physical exercise in healthy subjects. Sixty healthy men (17.2+/-1.71 years, BMI 23.2+/-2.31 kg m(-2), VO(2max) 54.7+/-6.48 ml kg(-1) min(-1)) took part in the study. The subjects performed a single maximal physical exercise on a bicycle ergometer. Blood for analyses was sampled three times: immediately before exercise, immediately after exercise, and in the 30th min of rest. Concentrations of uridine and hypoxanthine, xanthine and uric acid were determined in whole blood using high-performance liquid chromatography. We have shown in this study that the maximal exercise-induced increase of uridine concentration correlates with the post-exercise increase of uric acid concentration and systolic blood pressure. The results of our study show a relationship between uridine concentration in blood and uric acid concentration and blood pressure. We have been the first to demonstrate that a maximal exercise-induced increase in uridine concentration is correlated with the post-exercise and recovery-continued increase of uric acid concentration in healthy subjects. Thus, it appears that uridine may be an indicator of post-exercise hyperuricemia and blood pressure.
- GeneReviews®: Lesch-Nyhan Syndrome [BOOK]
- BOOKUniversity of Washington, Seattle: Seattle (WA)
- Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenti…
Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features, hypotonia and developmental delay, are evident by age three to six months. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonos) and pyramidal involvement (e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident. Cognitive impairment and behavioral disturbances emerge between ages two and three years. Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) is a hallmark of the disease. Overproduction of uric acid may lead to deposition of uric acid crystals or calculi in the kidneys, ureters, or bladder. Gouty arthritis may occur later in the disease. Related disorders with less severe manifestations include hyperuricemia with neurologic dysfunction but no self-injurious behavior and hyperuricemia alone, sometimes with acute renal failure.
New Search Next
- Enzymatic properties and physiological roles of cytosolic 5'-nucleotidase II. [Review]
- CMCurr Med Chem 2013; 20(34):4260-84
- Cytosolic 5'-nucleotidase II (cN-II) is an intracellular 5'-nucleotidase characterized by substrate specificity. It preferentially hydrolyzes 6-hydroxypurine nucleotides such as IMP and GMP over AMP …
Cytosolic 5'-nucleotidase II (cN-II) is an intracellular 5'-nucleotidase characterized by substrate specificity. It preferentially hydrolyzes 6-hydroxypurine nucleotides such as IMP and GMP over AMP or UMP. cN-II is allosterically activated by ATP and inhibited by inorganic phosphate. It also has phosphotransferase activity and transfers phosphate moieties from IMP or GMP to nonphysiological nucleoside analogues used to treat some viral infections or malignancies. The cN-II gene has a strikingly conserved primary structure from humans to nematodes and its activity has been detected in various animals including snails. Its activity is highest in the livers of birds, crocodiles, lizards and snakes. The activity in chicken liver increases 2-fold by feeding a high-protein diet. These results suggest that cN-II participates, through IMP dephosphorylation, in production of uric acid as the main end product of aminonitrogen in these animals. Some studies suggest that cN-II participates in dephosphorylation of IMP accumulated in cells of some tissues to diffusible inosine for reutilization by other tissues. It has also been proposed that cN-II, together with purine nucleoside phosphorylase and hypoxanthine-guanine phosphoribosyltransferase, constitutes the "oxypurine cycle", thus regulating intracellular phosphoribosyl pyrophosphate (PRPP) concentrations. As for intracellular dephosphorylation of AMP, another intracellular 5'-nucleotidase, cN-I, is supposed to participate, because it hydrolyzes AMP more preferentially than IMP or GMP. However, for the tissues, in which the expression of cN-I is very low or undetectable, e.g. liver or brain tissues, results have been obtained that suggest the participation of cN-II in intracellular dephosphorylation of AMP.