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Y Sidi

Publications and source records attributed to Y Sidi.

At least 109 records · Page 6Linked to original sources
PubMed1985

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

5-Amino-4-imidazolecarboxamide riboside 5'-monophosphate (ZMP) is an intermediate in the purine de novo synthetic pathway that may be further metabolized to inosine 5'-monophosphate, degraded to the corresponding nucleoside (5-amino-4-imidazole-carboxamide riboside; Z-riboside), or phosphorylated to the corresponding 5'-triphosphate (ZTP). Accumulation of ZTP in microorganisms has been associated with depletion of folate intermediates that are necessary for the conversion of ZMP to inosine 5'-monophosphate and has been postulated to play a regulatory role in cellular metabolism. We have shown the presence of Z-nucleotides in erythrocytes derived from five individuals with the Lesch-Nyhan syndrome. Erythrocyte folate levels were within the normal range, although guanosine triphosphate levels were significantly reduced below those in normal controls (P less than 0.01). A small amount of Z-nucleotide accumulation was also found in one individual with partial deficiency of the enzyme hypoxanthine guanine phosphoribosyltransferase and in two individuals with other disorders of purine overproduction. In contrast, no Z-nucleotides were detected in 13 normal controls or in three individuals with hyperuricemia on allopurinol therapy. We conclude that Z-nucleotide formation may result from markedly increased rates of de novo purine biosynthesis. It is possible that metabolites of these purine intermediates may play a role in the pathogenesis of the Lesch-Nyhan syndrome.

Aminoimidazole Carboxamide↗
PubMed1985

Differential metabolism of guanine nucleosides by human lymphoid cell lines.

Deficiency of the enzyme purine nucleoside phosphorylase is associated with a specific depletion of T cells which is presumably mediated by its substrate, 2'-deoxyguanosine. Inhibitors of this enzyme are therefore being developed as potential immunosuppressive agents. We have compared the effects of 8-aminoguanosine, a competitive inhibitor of purine nucleoside phosphorylase, on the metabolism of 2'-deoxyguanosine by human T lymphoblasts, B lymphoblasts, and mature T-cell lines. 8-Aminoguanosine markedly potentiates the accumulation of dGTP in T lymphoblasts, but results in increased GTP levels in B lymphoblasts and mature T cells. GTP accumulation is associated with ATP depletion of a magnitude similar to that seen with an inhibitor of de novo purine biosynthesis, but does not result in inhibition of either DNA or RNA synthesis. In contrast, direct inhibition of de novo purine biosynthesis sharply decreased the incorporation of [3H]uridine into both DNA and RNA. We conclude that the mechanism of cell damage resulting from prolonged accumulation of GTP appears to involve more than inhibition of de novo purine biosynthesis and consequent ATP depletion. Perturbations in guanine nucleotide pools resulting from partial inhibition of purine nucleoside phosphorylase activity in vivo could result in cellular toxicity not limited to the target T cell population.

Adenine Nucleotides↗
PubMed1985

Effects of guanine ribonucleotide accumulation on the metabolism and cell cycle of human lymphoid cells.

A deficiency of purine nucleoside phosphorylase activity is associated with marked depletion of T-lymphocytes which is felt to be mediated by accumulation and further metabolism of the purine nucleoside phosphorylase substrate, 2'-deoxyguanosine. Human T-lymphoblasts incubated in the presence of 2'-deoxyguanosine and the purine nucleoside phosphorylase inhibitor 8-aminoguanosine accumulate deoxyguanosine 5'-triphosphate whereas B-lymphoblasts and mature T4+-cell lines accumulate GTP under identical conditions. We have compared the effects of guanine ribo- and deoxyribonucleotide accumulation on the metabolism and cell cycle of the respective cell lines. Deoxyguanosine 5'-triphosphate elevations in T-lymphoblasts are associated with inhibition of [3H]uridine incorporation into DNA and a complete block at the G1-S interface of the cell cycle. In contrast 3- to 5-fold increases in guanosine 5'-triphosphate pools in B-lymphoblasts and mature T-cell lines do not inhibit [3H]uridine incorporation into DNA or RNA but do cause a pronounced slowing in the progression of cells through S phase. B-lymphoblasts deficient in the salvage enzyme hypoxanthine guanine phosphoribosyltransferase do not accumulate guanosine 5'-triphosphate from 2'-deoxyguanosine and progress normally through the cell cycle, demonstrating a requirement for guanine salvage to inhibit cell growth. Guanine ribonucleotide accumulation was also associated with inhibition of de novo purine biosynthesis and a moderate decline in adenine nucleotide pools but not with inhibition of protein synthesis or alterations in basal levels of 3':5'-cyclic adenosine monophosphate or 3':5'-cyclic guanosine monophosphate. We conclude that the accumulation of guanine ribonucleotides by actively cycling human lymphoid cells is associated with an increase in S-phase cells and inhibition of growth. This effect is distinctly different from that produced by 2'-deoxyguanosine 5'-triphosphate and should be taken into account in pharmacological studies with 2'-deoxyguanosine and its analogues.

Cell Cycle↗
PubMed1984

2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation.

Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP) results in selective and severe T lymphocyte depletion which is mediated by its substrate, 2'-deoxyguanosine. This observation provides a rationale for the use of PNP inhibitors as selective T cell immunosuppressive agents. We have studied the relative effects of the PNP inhibitor 8-aminoguanosine on the metabolism and growth of lymphoid cell lines of T and B cell origin. We have found that 2'-deoxyguanosine toxicity for T lymphoblasts is markedly potentiated by 8-aminoguanosine and is mediated by the accumulation of deoxyguanosine triphosphate. In contrast, the growth of T4+ mature T cell lines and B lymphoblast cell lines is inhibited by somewhat higher concentrations of 2'-deoxyguanosine (ID50 20 and 18 microM, respectively) in the presence of 8-aminoguanosine without an increase in deoxyguanosine triphosphate levels. Cytotoxicity correlates instead with a three- to fivefold increase in guanosine triphosphate (GTP) levels after 24 h. Accumulation of GTP and growth inhibition also result from exposure to guanosine, but not to guanine at equimolar concentrations. B lymphoblasts which are deficient in the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase are completely resistant to 2'-deoxyguanosine or guanosine concentrations up to 800 microM and do not demonstrate an increase in GTP levels. Growth inhibition and GTP accumulation are prevented by hypoxanthine or adenine, but not by 2'-deoxycytidine. 8-Aminoguanosine appears to effectively inhibit extracellular PNP activity; thus, it prolongs the extracellular half-life of 2'-deoxyguanosine and guanosine, but does not completely inhibit intracellular PNP activity in these lymphoid cells. As a result, 2'-deoxyguanosine and guanosine are phosphorolyzed and actively salvaged within the cell, accounting for the accumulation of GTP. Partial inhibition of PNP activity in vivo, therefore, may lead to nonselective cellular toxicity by a mechanism independent of dGTP accumulation.

B-Lymphocytes↗
PubMed1984

The activities of enzymes of purine metabolism in murine thymus dependent lymphocytes.

Measurement of the activities of purine metabolizing enzymes in murine T cell subpopulations showed that these activities differed markedly among T cells of different levels of functional maturity. The activities of adenosine deaminase and deoxyadenosine phosphorylation were highest in immature, PNA + thymocytes, while the activities of purine nucleoside phosphorylase, ecto-5'-nucleotidase and deoxyguanosine phosphorylation were highest in mature, splenic T cells. These enzymes' activities can be used as biochemical markers for T cell of different degree of maturation.

5'-Nucleotidase↗
PubMed1984

Hodgkin's and non-Hodgkin's lymphomas masquerading as "idiopathic" liver granulomas.

Three patients presented with liver granulomas and fever. An intensive investigation was initially negative. Corticosteroids were administered with dramatic clinical improvement. Ten months to 3 years later, upon tapering the corticosteroid dose, the initial manifestations reappeared. In two patients Hodgkin's lymphoma was discovered and in a third histiocytic lymphoma. Thus, the diagnosis of lymphoma should be considered in patients with idiopathic liver granulomas, fever, and hepatosplenomegaly without lymph node enlargement, who respond initially to steroid administration but relapse upon tapering the dose.

Adult↗
PubMed1983

Systemic lupus erythematosus and lymphoma. A family study.

After 3 years of treatment with azathioprine and prednisone, immunoblastic lymphoma appeared in a patient with systemic lupus erythematosus. An increased incidence of immunological aberrations and malignancies was found in her family and their relation to the pathogenesis of this patient's diseases is discussed.

Adult↗
PubMed1983

Characterization of thymocyte subpopulations by enzymatic markers.

The activities of ecto-5'-nucleotidase (E5N), deoxyadenosine kinase (dAK) and deoxyguanosine kinase (dGK), were determined in thymocyte subpopulations, separated by peanut agglutinin (PNA). The activity of dAK in the PNA+ (agglutinated by PNA) thymocyte subpopulation was 2.5-fold that in the PNA- subpopulation. The activities of E5N and of dKG were found to be higher in the PNA- than in the PNA+ subpopulation by 15- and 4-fold, respectively. The activity of these enzymes can therefore be utilized to characterize the thymocyte subpopulation. In addition, since PNA+ cells are considered to be young immature precursors of the PNA- thymocytes, the activity of these enzymes may serve also as markers for the degree of maturation of the T cells.

5'-Nucleotidase↗
PubMed1983

Serial two-dimensional echocardiography in infective endocarditis of the pulmonic valve.

Infective endocarditis was diagnosed in a 15-yr-old patient following closure of a patent ductus arteriosus several weeks previously. Pulmonic valve vegetations were detected by both M-mode and two-dimensional echocardiograms. The serial echocardiographic examinations revealed the emergence of a vegetation on the pulmonic valve, a marked decrease in its size subsequent to pulmonary embolism, reemergence of a vegetation upon relapse of the disease and its resolution 4 mo later. The echocardiographic findings and their correlation to the various stages of the disease are described.

Adolescent↗