Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine or pyrimidine metabolism

Simmonds, H. Anne; Fairbanks, Lynette D.; Morris, Gareth; Webster, Dianne; Harley, Eric H.

doi:10.1016/0009-8981(88)90145-3

Cited by 93 publications

(52 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14 It is likely that GTP depletion is an important mechanism that results in the severe neurological manifestations in purine pathway disorders as demonstrated in the past for HGPRT deficiency (Lesch-Nyhan syndrome) and infantile PRS-1 superactivity. 14,15 …”

Section: Discussionmentioning

confidence: 99%

Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

et al. 2014

View full text Add to dashboard Cite

PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal a-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C4T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Abbreviations: PN-I, pyrimidine 5'-nucleotidase type I; PN-II, pyrimidine nucleotidase type II; 5'-AZT-MP, 3'-azido-3'-deoxy-thymidine-5'-monophosphate; 5'-Ara-CMP, cytosine-ß-D-arabinofuranoside-5'-monophosphate; 5'-FdUMP, 5-fluoro-deoxy-uridine-5'-monophosphate; AZT, 3'-azido-3'-deoxy-thymidine; AraC, cytosine-i?-D-arabinofuranoside; 5FdUrd, 5-fluoro-2'-deoxy-uridine; DTT, dithiothreitol; p-CMB, /)-chloromercuribenzoate; DTNB, 5,5'-dithiobis(2'-nitrobenzoic acid) Such a condition determines a marked erythrocyte accumulation of pyrimidine nucleotides, detectable both by spectrophotometrically [1] and by a HPLC-based assay [4], and is accompanied by a distinctive basophilic stippling of erythrocytes upon Wright staining of blood smears [1]. Furthermore it has been shown [3,5,6] that affected patients, although defective in erythrocyte 5'-nucleotidase activity towards UMP, CMP and dCMP, conserved normal activity toward dUMP and dTMP.…”

Section: Introductionmentioning

confidence: 99%

Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides

et al. 1997

View full text Add to dashboard Cite

Two cytoplasmic forms of pyrimidine nucleotidase (PN-I and PN-II) have been purified from human erythrocytes to apparent homogeneity and partially characterized. They preferentially hydrolyse pyrimidine 5'-monophosphates and 3'-monophosphates respectively. PN-I and PN-II operate as interconverting activities, capable of transferring the phosphate from the pyrimidine nucleoside monophosphate donor(s) to various nucleoside acceptors, including important drugs like 3'-azido-3'-deoxy-thymidine (AZT), cytosine-ß-D-arabinofuranoside (AraC) and 5-fluoro-2'-deoxy-uridine (5FdUrd), pyrimidine analogues widely used in chemotherapy. Kinetic analysis showed linear behaviour for both PN-I and PN-II. PN-I phosphotransferase activity revealed higher affinity for oxynucleosides with respect to deoxy-nucleosides, whereas the contrary seems to be true for PN-II. These results show for the first time that soluble pyrimidine nucleotidases are endowed with pyrimidine-specific phosphotransferase activity.

show abstract

“…mean difference not significantly different from zero at the 5% level). 4. The 95% limits of agreement is (bias ± 2 s.d.)…”

Section: Impedance Cardiographymentioning

confidence: 92%

“…In addition to the intracellular formation of ddA-TP, didanosine may be broken down to hypoxanthine and uric acid by the enzymes purine nucleoside phosphorylase (PNP) and xanthine oxidase [3]. As PNP is found in relatively high concentrations in human erythrocytes [4] we have previously investigated the metabolism of ddl in vitro using human blood [5] Each blood sample was divided into two aliquots, one was centrifuged immediately (3000 rev min-' for 10 min) and the other was left at room temperature and centrifuged when the pharmacokinetic study was completed. The separated plasma samples were exposed to a temperature of 580 C for 30 min to inactivate the human immunodeficiency virus [6] and then analysed for ddl using a commercial radioimminoassay (Sigma, London).…”

Section: Metabolism Of Didanosine (Ddl) Pharmacokinetic Implicationsmentioning

confidence: 99%

Metabolism of didanosine (ddI) by erythrocytes: pharmacokinetic implications [letter]

Barry

Back

Ormesher

et al. 1993

Brit J Clinical Pharma

View full text Add to dashboard Cite

Didanosine is a nucleoside analogue with potent inhibitory effects against the human immunodeficiency virus (HIV) [1]. It is converted within target cells to its active form ddA-triphosphate, which is thought to act as a chain terminator and inhibitor of reverse transcriptase [2]. In addition to the intracellular formation of ddA-TP, didanosine may be broken down to hypoxanthine and uric acid by the enzymes purine nucleoside phosphorylase (PNP) and xanthine oxidase [3]. As We have now investigated this possibility in a pharmacokinetic study of three men who were infected with HIV and who took ddl (250 mg twice daily) following zidovudine intolerance. Approval for the study was granted by the local Ethics Committee and all patients provided written informed consent. Each patient attended for study on two occasions separated by at least 2 weeks. After an overnight fast and following the insertion of an intravenous cannula, blood samples were taken at 15 min intervals for 2 h, half-hourly for another 2 h, and at 5 and 6 h after didanosine 250 mg.Each blood sample was divided into two aliquots, one was centrifuged immediately (3000 rev min-' for 10 min) and the other was left at room temperature and centrifuged when the pharmacokinetic study was completed. The separated plasma samples were exposed to a temperature of 580 C for 30 min to inactivate the human immunodeficiency virus [6] and then analysed for ddl using a commercial radioimminoassay (Sigma, London). Plasma samples were initially diluted 1:100 with blank plasma. The assay has a limit of detection of less than 1 nm. The interassay coefficient of variation was less than 10% at a concentration of 10 nm. Figure 1 shows the plasma drug concentrations for samples centrifuged immediately and those centrifuged after some delay, i.e. at the end of the study period. Although the latter were left for variable times (early samples left longer than later samples) this procedure reflects what will often happen in clinical studies.Plasma concentrations of ddl were consistently lower in samples whose centrifugation was delayed, with the greatest difference in early samples and little difference in later samples. 22% from 6.69 ± 1.12 to 5.21 ± 0.86 p,mol 1-1 h (mean + s.d; P < 0.001, Student's paired t-test; 95% CI of the difference 1.00 to 1.95). The maximum plasma drug concentration (Cmax) was reduced from 3.86 ± 0.66 to 3.10 ± 0.77 ,umol I' (P <0.01; 95% CI of the difference 0.22 to 1.30).The implications for pharmacokinetic studies involving ddI are clear. If blood samples are taken and left at room temperature (or higher) for any length of time, concentrations of ddl will be underestimated because of its continued breakdown in blood. Therefore, blood samples should be centrifuged immediately and the plasma separated to minimise breakdown by PNP.

show abstract

Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine or pyrimidine metabolism

Cited by 93 publications

References 14 publications

Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides

Metabolism of didanosine (ddI) by erythrocytes: pharmacokinetic implications [letter]

Contact Info

Product

Resources

About