PURINE AND PYRIMIDINEMETABOLISM IN MAN X

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University of New York at Buffalo

IRUN R. COHEN, The Weizmann Institute of Science

DAVID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research

RODOLFO PAOLETTI, University of Milan

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PURINE AND PYRIMIDINEMETABOLISM IN MAN X

Edited by

Esther Zoref-ShaniTel-Aviv UniversityTel -Aviv, Israel

and

Oded SperlingRabin Medical CenterPetah-Tikva, Israel andTel-Aviv UniversityTel-Aviv, Israel

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PREFACE

This volume contains articles presented at the Xth InternationalSymposium on Purines and Pyrimidines in Man, held on May 14-19, 2000 inTel-Aviv, Israel. The first symposium in this series took place in Tel-Aviv in1973. Since then, the symposium has been held every three years in differentparts of the world, including Europe, USA and Japan. The participants, inthis series of symposia, are characterised by a wide interest in the variousaspects of purines and pyrimidines in man, which include biochemistry,genetics, pharmacology, physiology, clinics, etc. Presentations in thesymposia include clarification of metabolic pathways, characterisation ofenzyme structure and kinetics and discoveries of new inborn errors ofmetabolism and suggestions for new therapeutic approaches for these inbornerrors. In addition, development of new purine and pyrimidine derivativesfor the treatment of cancer and viral diseases, and many more subjects ofmutual interest were brought to the fore. With the development oftherapeutic means and of new research tools, we have witnessed changes inthe areas of interest. The interest in gout and uric acid urolithiasis haslessened, whereas molecular aspects, the role of purine and pyrimidinesubstances in neurotransmission and in purinergic signaling appear to gaingreater interest. The articles, included in this volume, contain new datapertaining to the various aspects detailed above.

We thank the Local Organising Committee, the International AdvisoryBoard and the Symposium Secretariat for their outstanding dedicationtowards making this symposium a success. We look forward to the XIth

symposium, to be held in Amsterdam, in 2003.

The Editors

v

CONTENTS

I. INBORN ERRORS OF PURINE METABOLISM

1. Purine and Pyrimidine Metabolism Between Millennia: What HasBeen Accomplished? What Has To Be Done? 1

G. Van den Berghe

2. Cell Type-Specific Differential Expression of Human5Phosphoribosylpyropshosphate Synthetase (PRPS) Genes

M.A. Becker, M. Ahmed

3. Mutations in the Hypoxanthine-GuaninePhosphoribosyltransferase Gene in Spanish HPRT DeficientFamilies 11

R.J. Torres, F.A. Mateos, J. Molano, B.S. Gathoff, J.P. O’Neill,R.M. Gundel, L. Trombley, J.G. Puig

4. The Spectrum of Hypoxanthine-Guanine Phosphoribosyltransferase(HPRT) Deficiency 15

J.G. Puig, R.J. Torres, F.A. Mateos, T. Ramos, A.S. Buno, J.Arcas

5. Deletion in the Hypoxanthine Phosphoribosyltransferase GeneCaused by ALU-ALU Recombination in Two JapanesePatients with Lesch-Nyhan Syndrome 23

M. Mizunuma, S. Fujimori, K. Kaneko, N. Kamatani

vii

viii Contents

6. Novel Genetic Mutations Responsible for the HPRT Deficiencyand the Clinical Phenotypes in Japanese

Y. Yamada, M. Nomura, H. Kitoh, N. Wakamatsu, N.Ogasawara

29

7. Adenoviruses Encoding HPRT Correct the BiochemicalAbnormalities Fully Only in HPRT-Deficient Human CellLines: Importance of Species Differences 35

T. Southgate, D. Bain, L.D. Fairbanks, A. Morelli, A. Larregina,H.A. Simmonds, M. Castro, P. Lowenstein

8. Biochemical and Immunological Abnormalities in PurineNucleoside Phosphorylase Deficient Mice

E. Arpaia, Y. Gu, I. Dalal, S. Kelly, M. Hershfield, C.M.Roifman, A. Cohen

41

9. Carrier Erythrocyte Entrapped Adenosine Deaminase Therapy inAdenosine Deaminase Deficiency 47

B.E. Bax, M.D. Bain, L.D. Fairbanks, H.A. Simmonds, A.D.Webster, R.A. Chalmers

10.ADA Activity and dATP levels in Erythrocytes after BoneMarrow Transplantation

L.D. Fairbanks, H.A. Simmonds, J.A. Duley, B. Gaspar, T.Flood, C. Steward

51

11. Adenosine Deaminase-Deficient Mice: Models for The Study ofLymphocyte Development and Adenosine Signaling 57

M.E. Aldrich, M.R. Blackburn, S.K. Datta, R.E. Kellems

12. Inhibition of Fetal Thymic Caspases Abrogates the Consequencesof Adenosine Deaminase Deficiency 65

C.J. Van De Wiele, S.W. Hooker, A.B. Laurent, J.G. VaughnM.R. Blackburn, R.E. Kellems, M.S. Hershfield, L.F.Thompson

13. Erythrocyte AMP Deaminase Deficiency in Japanese: ACompound Heterozygote Responsible for the CompleteDeficiency 71

Y. Yamada, H. Goto, N. Ogasawara

Contents ix

14. Effect of Uridine Administration to a Patient with75Adenylosuccinate Lyase Deficiency

C. Salerno, C. Crifo, P. Curatolo, F. Ciardo

15. Adenylosuccinate Lyase Deficiency: From the Clinics toMolecular Biology 79

S. Marie, V. Race, M.F. Vincent, G. Van den Berghe

16. Polymorphic Markrs in the XDH Gene as Diagnostic Tools forTyping Classical Xanthinuria 83

A. Lagziel, D. Levartovsky, O. Sperling, K. Ichida, H. Peretz

17. NAPDD Patients Exhibit Altered Electrophoretic Mobility ofCytosolic 5’-Nucleotidase

M. Trifilo, T. Page

18. Purines, Lactate and Myoinositol in CSF Might ReflectExcitotoxicity in Inherited Metabolic Disorders

A. Latini, L. Larovere, R. Dodelson de Kremer

19. Cerebrospinal Fluid Purines, Pyrimidines, Organic Acids andAmino Acids in Neonatal Citrullinaemia 97

87

91

L. Larovere, A. Latini, C. Depetris-Boldini, C.E. Coronel, R.Dodelson de Kremer

II. PURINE METABOLISM

20. Purine Nucleotide Catabolism in Rat Liver 103E. Marinello, R. Pagani, L. Arezzini, B. Porcelli, G. Cinci, L.

Terzuoli

21. Further Refinement on the Engineering of AdenosinePhosphorylase from Purine Nucleoside Phosphorylase 107

J.T. Maynes, R.G. Yuan, B.M. Phipps, S.A. Litster, K. Leung,F.F. Snyder

22. Human Guanine Deaminase: Cloning, Expression andCharacterization 111

F.F. Snyder, R.G. Yuan, J.C. Bin, K.L. Carter, D.J. McKay

x Contents

23. The Human NUTD Family of Nucleotide Hydrolases 115A.G. McLennan, J.L. Cartwright, L. Gasmi

24. Inhibitors of NTPDase: Key Players in the Metabolism ofExtracellular Purines 119

F.P. Gendron, E. Halbfinger, B. Fischer, A.R. Beaudoin

25. Apoptosis-Inducing Cleavage of Caspases by Trimidox, anInhibitor of Ribonucleotide Reductase 125

M.Fritzer-Szekeres, C. Luxbacher, Z. Horvath, M. Grusch,G. Krupitza, H.L. Elford, T. Szekeres

III. GOUT AND HYPERURICEMIA

26. Increased Visceral Fat Accumulation in Patients with PrimaryGout 131

S. Takahashi, T. Yamamoto, Z. Tsutsumi, Y. Moriwaki, T. Hada

27. Serum Uric Acid Levels and Microalbuminuria in MildHypersensitive Patients 135

R.J. Torres, M.A. Martinez, T. Sancho, A.. Moreno, R. Cabrera,A. Aguirre, A. Torre, A. Nevado, J.G. Puig

IV. PURINES IN CARDIOLOGY

28. Guanosine-5’-Triphosphate Increases in Red Blood Cells of HeartTransplant Recipients Treated with Mycophenolate Mofetil 139

A. Griesmacher, G. Weigel, G. Seebacher, M.M. Müller

29. Adenine Incorporation in Endothelial Cells 145K.K. Kalsi, M. Zych, E. Slominska, Z. Kochan, M.H. Yacoub,

R.T. Smolenski,

30. TNF-α Reduces the Activity of Ecto-5'-Nucleotidase in HumanEndothelial Cells 149

K.K. Kalsi, C Lawson, A. McCormack, Z. Kochan, M.H.Yacoub, R.T. Smolenski

Contents xi

31. Influence of Age and Heat Stress on Cardiac Function andNucleotide Levels

C.C. Gray, R.T. Smolenski, M. Amrani, G.L. Taylor, M.H.Yacoub

153

32. The Role of 5’-Deoxy-5’-Methylthioadenosine Phosphorylase inCardiac Adenosine Breakdown and Adenine Production 159

E M. Slominska, K.K. Kalsi, M.H. Yacoub and K.T. Smolenski

33. The Effect of Adenosine Metabolism Inhibition and NucleotidePrecursor Supply on Adenosine Production in Human HeartEndothelial Cells 163

R.T. Smolenski, K.K. Kalsi, C.C. Gray, M. Zych, Z. Kochan,M.H. Yacoub

34. Enhanced Endogenous Adenosine Production and Protection ofthe Heart after Transplantation 167

R.T. Smolenski, O. Raisky, K.K. Kalsi, H. Abunasra, J.Jayakumar, K. Suzuki, M.H. Yacoub

35. Role of Bovine Hemoglobin Enriched Cardioplegia inMyocardial Preservation 171

E. Marinello, A. Tabucchi, F. Miraldi, A. Barretta, F. Rosi, F.Carlucci

V. RENAL HANDLING OF PURINES

36. Identification of the Potential Sensitive Urate/PAH Transporterfrom LLC-PK1 Kidney Epithelial Cells 175

F. Spitzenberger, J. Graessler, H-E. Schroeder

37. Genomic Structure of Galectin-9 Gene. Mutation Analysis of aPutative Human Urate Channel/Transporter 179

J. Graessler, F. Spitzenberger, A. Graessler B. Parpart, E.Kuhlisch, S. Kopprasch, H-E. Schroeder

38. Effect of Losartan and Furosemide on the Urinary Excretion ofOxypurinol and Uric Acid 185

T. Yamamoto, Y. Moriwaki, S. Takahashi, Z. Tsutsumi, T. Hada

xii Contents

VI. PURINERGIC SIGNALLING

39. P2y and P2x Purinoceptors Are Respectively Implicated inEndothelium-Dependent Relaxation and EndotheliumIndependent Contraction In Human Corpus Cavernosum 189

F. Staerman, M. Shalev, A. Legrand, B. Label, B. Saïag

40. ATP-Triggered Calcium Signals in Human Neutrophils 197C. Crifo, E. Capuozzo, J. Ovadi, C. Salerno

41. The Role of A1/A3 Adenosine Receptor Activation in Reductionof Cardiomyocyte Injury Caused by Hypoxic Stress and inInduction of Apoptosis in Rat Cardiomyocyte Cultures 201

A. Shainberg, N. Safran, N. Balas, T. Zinman, A. Isaac, K.Schwab, B. Akabayov, V. Shneyvays

42. Blockade of A1 Receptors by Caffeine Induces C-fos, Zif-268 andarc Expression in the Striatum through DifferentInteractions with the Dopamine System 207

D. Dassesse, J.-M.. Vanderwinden, I. Golberg, J.-J.Vanderhaeghen, S.N. Schiffmann

43. Role of KATP Channels in the Induction of Ischemic Toleranceby the ‘Adenosine Mechanism’ in Neuronal Cultures 217

A. Reshef, O. Sperling, E. Zoref-Shani

44. Adenosine-Induced Caspase Activity in N1E-115 Cells 223S.M. Schrier, A.P. Ijzerman, G.J. Mulder, J.F. Nagelkerke

45. Effect of Adenosine Receptor Agonists and Antagonists onTransport of Adenosine in Bovine Heart MicrovascularEndothelial Cells 227

J. Barankiewicz

VII. INBORN ERRORS OF PYRIMIDINE METABOLISM

46. Defects of Pyrimidine Degradation: Clinical, Molecular andDiagnostic Aspects

A.H. van Gennip, A.B.P. van Kuilenburg233

Contents

47. Confirmation of the Enzyme Defect in the First Case of

A.B.P. van Kuilenburg H. van Lenthe, G. Göhlich-Ratmann, B.

48. Dihydropyrimidine Dehydrogenase (DPD) Deficiency: Novel

A.B.P. van Kuilenburg, J. Haasjes, R. Meinsma, H.R. Waterham,

49. Dihydropyrimidine Dehydrogenase Deficiency and 5-Fluorouracil Associated Toxicity 251

A.B.P. van Kuilenburg, J. Haasjes, H. Van Lenthe, L.Zoetekouw, H.R. Waterham, P. Vreken, A.H. van Gennip

50. Isoforms of Human CTP Synthetase 257

A.H. van Gennip

β-Ureidopropionase Deficiency 243

Assmann, G.F. Hoffmann, C. Brautigam, A.H. van Gennip

Mutations in the DPD Gene 247

P. Vreken, A.H. van Gennip

A.B.P. van Kuilenburg, R. Meinsma, P. Vreken, H.R. Waterham,

VIII. PYRIMIDINE METABOLISM

51. Polyclonal Antibodies Against the Ultrafast MultisubstrateDeoxy-ribonucleoside Kinase from Drosophila Melanogaster

W. Knecht, B. Munch-Petersen, J. Piskur

52. Inhibition and Localizaton of Human and Rat DihydroorotateDehydrogenase

263

267W. Knecht, M. Loffler

IX. ONCOLOGY AND CHEMOTHERAPY

53. 6-Mercaptopurine: Efficacy and Bone Marrow Toxicity inChildhood Acute Lymphoblastic Leukemia

R.A. De Abreu, L.H.J. Lambooy, K. Ahment, C. Brouwer, J.JKeizer-Garritsen, J.P.M. Bokkerink, F.J.M. Trijbels

54. Recovery of SK-N-BE(2)C Cells from Treatment withCyclopentenyl Cytosine

271

277J. Bierau, A.H. van Gennip, A.B.P. van Kuilenburg

xiii

xiv Contents

55. Effect of Phosphorylation on Deoxycytidine Kinase Activity 281T. Spasokoukotskaja, Z. Csapo, M. Sasvari-Szekely, S. Virga, I.

Talianidis, S. Eriksson, M. Staub

56. The Role of Deoxycytidine Kinase in Gemcitabine Cytotoxicity 287C.L. van der Wilt, J.R. Kroep, A.M. Bergman, W.J.P. Loves, E.

Alvarez, I. Talianidis, C.J. van Groeningen, H.M. Pinedo, G.J. Peters

57. Thymidine Phosphorylase in Angiogenesis and Drug Resistance 291G.J. Peters, M. De Bruin, M. Fukushima, B. Van Triest, K.

Hoekman, H. M. Pinedo, S. P. Ackland

58. Secretion of Thymidine by Hybridoma Cells 295B. Spilsberg, F. Rise, D. Petersen, J. Nissen-Meyer

59. Thymidylate Synthase Inhibition Induces P53 Dependent andIndependent Cell Death 303

H.H.J. Backus, D. Wouters, C.L. van der Wilt, C.M. Kuiper, C.J.van Groeningen, H.M. Pinedo, G.J. Peters

60. 2-Chlorodeoxyadenosine (2-CDA) Does Not Change theExpression of FAS Antigen on Chronic LymphocyticLeukaemia Cells 307

J. Gora-Tybor, E. Lech-Maranda, J.Z. Blonski, T. Robak

61. Cyclopentenyl Cytosine Increases the Phosphorylation andIncorporation into DNA of Arabinofuranosyl Cytosine in aMyeloid Leukemic Cell-Line 311

A.C. Verschuur, A.H. van Gennip, R. Leen, P.A. Voute, A.B.P.van Kuilenburg,

62. Cyclopentenyl Cytosine Induces Apoptosis and SecondaryNecrosis in a T-Lymphoblastic Leukemic Cell-Line

A.C. Verschuur, A.H. van Gennip, J. Brinkman, P.A. Voûte,A.B.P. van Kuilenburg,

319

63. Thiopurine Methyltransferase: Activity and Genotyping inPatients with Acute Lymphoblastic Leukemia 327

C. Brouwer, J.J. Keizer-Garritsen, L.H.J. Lambooy, K. Ament,P.G.J.H. Ter Riet, R.A. De Abreu, J.P.M. Bökkerink,E.R. Van Wering, A. Van Der Does-Van Den Berg, A.J.P.Veerman, J.P.M.F. Trijbels

Contents xv

64. Hyperthermy Increase the Phosphorylation and Decrease theIncorporation of Nucleosides into DNA

G. Keszler, Z. Csapo, T. Spasokoutskaja, M. Sasvari-Szekely,S. Virga, A. Demeter, S. Eriksson, M. Staub

65. Purine Nucleotide Metabolism in Chronic LymphocyticLeukemia Lymphocytes

E. Marinello, F. Carlucci, F. Rosi, A. Tabucchi

66. Inhibition of DNA Methylation by 5-Aza-2’-DeoxycytidineCorrelates with Induction of K562 Cells Differentiation

K. Fabianowska-Majewska, D. Wyczechowska, M. Czyz

67. Evidence of Inhibition of DNA Methylation by FludarabineD. Wyczechowska, M. Czyz, K. Fabianowska-Majewska

68. The Cytotoxic Effect of Purine Riboside on Cos-7 CellsK. Tkacz, M. Cioroch, A.C. Skladanowski, W. Makarewicz

69. Methylated and Non Methylated Thiopurine Nucleotide Ratio(Me6-Mpn/6-Tgn): Usefulness In The Monitoring OfAzathioprine Therapy?

R. Boulieu, T. Dervieux, I. Gallant, M. Sauviat, M. Bertocchi,J.F. Mornex,

X. METHODS

70. Organ Preservation During Experimental Liver TransplantationE. Marinello, A. Tabucchi, F. Rosi, G. Gerunda, R. Merenda, R.

Ballarin, D. Neri, F. Carlucci

333

339

343

349

355

361

369

71. Extraction and Purification of Ecto-5'-Nucleotidase from HumanLymphocytes 373

E. Marinello, F. Rosi, A. Tabucchi, F. Carlucci, G. Cinci, M.Coli, A. Floridi, C. Fini

72. HPLC/ESI Tandem-MS of Liquid Urine or Urine Soaked FilterPaper Strips for the Detection of Thymine-Uraciluria andDihydropyrimidinuria 377

A.H. Van Gennip, H. Van Lenthe, T. Ito, A.H. Bootsma, A.C.Van Cruchten, Y. Wada, A.B.P. Van Kuilenburg

xvi Contents

73. Screening for Purine and Pyrimidine Disorders using Dried UrineSpots

L.D. Fairbanks, E. Escuredo, J.A. Duley, H.A. Simmonds

Determination of Methylated Purine Bases in Urine from HealthySubjects 389

E. Marinello, M.C. Di Pietro, R. Leoncini, G. Liso, R. Guerranti,G. Cinci, D. Vannoni

Decrease in Urinary Uric Acid Concentrations after UrineStorage 393

Y. Moriwaki, T. Yamamoto, S. Takahashi, J-I. Yamakita, Z.Tsutsumi, T. Hada

Mass Spectrometry for Analysis of Purine and PyrimidineCompounds

K. Lemr, T. Adam, P. Frycak, D. Friedecky399

405

415

383

74.

75.

76.

Author Index

Subject Index