Table Of ContentHandbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 51
Editorial Board
G.V. R. Born, Cambridge . A. Farah, Rensselear, NY
H. Herken, Berlin . A. D. Welch, Memphis, TN
Advisory Board
S. Ebashi . E. G. Erdos· V. Erspamer . U. S. von Euler· W. S. Feldberg
G. B. Koelle· O. Krayer . M. Rocha e Silva· J. R. Vane· P. G. Waser
W. Wilbrandt
Uric Acid
Contributors
W 1. Arnold . M. A. Becker . 1. M. Brogard . F. L. Coe
WH.Dantzler . H.S.Diamond . G.B.Elion
B. T. Emmerson· N. H. Ertel· 1. H. Fox· J. F. Henderson
G.H.Hitchings . E.WHolmes . WA.Katz . G.Peters
F. Roch-Ramel . H. R. Schumacher . P. A. Simkin
L. B. Sorensen . l. Spilberg . A. Stahl . 1. Stahl . T. H. Steele
l.H.Talbott . M.Tatibana . S.C.Wallace . TsJ\i-FanYii
Editors
William N. Kelley
Irwin M.Weiner
With 114 Figures
Springer-Verlag Berlin Heidelberg New York 1978
WILLIAM N. KELLEY, MD, Professor and Chairman
Department of Internal Medicine,
University of Michigan, Medical School, Ann Arbor, MI 48109, USA
IRWIN M. WEINER, MD, Professor and Chairman
Department of ~athology, Upstate Medical Center, Syracuse, NY 13210, USA
ISBN-13: 978-3-642-66869-2 e-ISBN-13: 978-3-642-66867-8
DOl: 10.1007/978-3-642-66867-8
Library of Congress Cataloging in Publication Data. Main entry under title: Uric acid. (Handbook of Experimental
Pharmacology; v. 51) Includes bibliographies and· indexes. 1. Gout. 2. Uric acid metabolism. I. Arnold, William James,
1928-. II. Kelley, William N. III. Weiner, Irwin M., 1930-. QP905.H3 vol. 51 [RC629] 615'.I'08s [616'.6] 77-28641
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned
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© by Springer-Verlag Berlin Heidelberg 1978.
Softcover reprint of the hardcover 1st edition 1978
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general
use.
2122/3130-543210
Preface
Uric acid has attracted the attention of scientists from a broad spectrum of
disciplines, and in recent years dramatic progress has occurred within many of these
disciplines. This volume is designed to fill void in the field. Major works in the past
five years have provided comprehensive reviews of disorders of uric acid metabolism
for the clinical (1-3) as well as short reports of recent progress for the interested
scholar (4, 5). In Uric Acid the reader will find extensive reviews of relevant topics
selected largely by virtue of recent progress in the field and written by those who,
to a considerable extent, qre responsible for that progress.
Seven chapters are dedicated to a description of uric acid synthesis, its control,
diseases resulting from aberrations in the pathway, and effects of intermediates and
end products of this pathway on other metabolic processes. The next five chapters
describe our current understanding of the mechanisms by which uric acid is elimi
nated by the organism. Then seven chapters review the factors responsible for the
human "disease" produced by uric acid in the joints and kidneys. The final four
chapters provide a summary of therapeutic approaches to control gout, the most
important disease caused per se by uric acid.
This book is not designed to be totaily comprehensive. Potentially relevant areas
which are not covered extensively include epidemiology, genetics, hypouricemia,
and management of asymptomatic hyperuricemia. On the other hand, some repeti
tion has been allowed where this was important for emphasis or continuity. This
style should enhance the overall value of the volume.
WILLIAM N. KELLEY
I. M. WEINER
Table of Contents
Biochemistry and Physiology of Uric Acid: Production
CHAPTER 1
Uric Acid: Chemistry and Synthesis. G. H. HITCHINGS. With 10 Figures
A. Introduction 1
B. Structure 2
C. Properties . 3
D. Synthesis 4
I. Synthesis from Imidazoles 6
II. One-Pot Synthesis . 7
E. Biosynthesis of Purines 8
F. Uricotelism . . . . . 11
G. Uricolysis . . . . . . 12
H. Measurement of Uric Acid Synthesis in Man 12
J. Uric Acid Formation from Purines 13
References 16
CHAPTER 2
Regulation of Biosynthesis De Novo. E. W. HOLMES, JR. With 7 Figures
A. Introduction ............. . 21
B. Rate-Limiting Step . . . . . . . . . . . . 22
C. Enzymatic Activities Leading to PRA Synthesis 26
D. Properties of Human PP-ribose-P Amidotransferase 28
E. Studies with Intact Cells 31
F. Studies In Vivo 35
G. Conclusion 37
References . . . . 38
VIII Table of Contents
CHAPTER 3
Purine Salvage Enzymes. W.J.ARNOLD
A. Introduction ........................ 43
B. Normal Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) 44
I. Assay Methods and Kinetic Properties 44
II. Physical Properties . . . . . . . . . . . . . . . . 46
III. Role in Cellular Transport of Purines . . . . . . . . 48
C. Clinical Syndromes Associated with a Deficiency of H G PRT 48
I. Lesch-Nyhan Syndrome . . . . . . . . . . . . . . 49
1. Characteristics of the Mutant HGPRT in Patients with the
Lesch-Nyhan Syndrome. . . . . . . . . . 50
2. Inheritance of HGPRT . . . . . . . . . . . . 53
3. Pathogenesis of the Neurobehavioral Disorder . . 54
4. Secondary Metabolic and Enzymatic Abnormalities 55
II. Partial Deficiency of HGPRT .......... 58
1. Characteristics of the Mutant HGPRT Enzyme in Patients with a
Partial Deficiency of HGPRT Activity . . . . . 58
2. Inheritance of Partial H G PRT Deficiency . . . . 59
3. Secondary Metabolic and Enzymatic Abnormalities 60
D. Normal Adenine Phosphoribosyltransferase (APRT) 60
I. Assay Methods and Kinetic Properties 60
II. Physical Properties . . . . . . . . . . . . . 63
III. Role in Cellular Transport of Purines . . . . . 63
E. Clinical Syndromes Associated with a Deficiency of APRT 64
I. Partial Deficiency of APRT . . . . . . . . . . . 64
1. Characteristics of the APRT Enzyme in Patients with a Partial
Deficiency ..................... 64
2. Metabolic Abnormalities Associated with a Partial APRT
Deficiency .......... . 65
II. Complete Deficiency of APRT Activity 66
References 66
CHAPTER 4
Purine Nucleotide Interconversions. J. F. HENDERSON. With 1 Figure
A. Pathways of Purine Nucleotide Interconversion . . . . . . . . . . . . 75
B. Regulation of Enzymes of Purine Nucleotide Interconversion in Intact
Mammalian Cells ......... 77
I. Enzyme Amount and Localization 78
II. Substrate Concentrations . . . . 79
III. Alternative Pathways of Substrate Metabolism 82
IV. Effects of Other Metabolites . . . . . . . . 83
Table of Contents IX
C. Functions of the Reactions of Purine Nucleotide Interconversion
in Mammalian Cells. . . . . . . . . . . . . . . 84
I. Biosynthesis of A TP and GTP . . . . . . . . 84
II. Balance Between ATP and GTP Concentrations 86
III. Catabolism of Adenine and Guanine Nucleotides 86
IV. Deamination of Amino Acids ....... . 86
D. Effects of Drugs on the Reactions of Purine Nucleotide Interconversion 87
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
CHAPTER 5
Degradation of Purine Nucleotides. I. H. Fox. With 7 Figures
A. Introduction ............. 93
B. Reactions of Purine Nucleotide Degradation 93
C. Properties of Purine Catabolic Enzymes . . 95
I. 5'-Nucleotidase (E.C.3.1.3.5) and Other Phosphatases 95
II. Purine Nucleoside phosphorylase (E.C.2.4.4.1) 101
III. Adenosine Deaminase (E.C.3.5.4.6) 102
IV. Guanine Deaminase (E.C.3.5.4.3) . . . . 105
V. Xanthine Oxidase (E.C.1.2.3.2) . . . . . 106
D. Regulation of Purine Nucleotide Degradation. 108
E. Inborn Errors of Purine Nucleotide Degradation 112
I. Adenosine Deaminase Deficiency . . . . . 112
II. Purine Nucleoside Phosphorylase Deficiency 112
III. Xanthinuria . . . . . . . . . . . . . . 113
IV. Other Disorders . . . . . . . . . . . . 113
F. Relationship of Purine Nucleotide Degradation to Immune Function 114
G. Other Relationships to Purine Nucleotide Degradation 115
H. Conclusions 116
References . . . . . . . . . . . . . . . . . .. . . . 116
CHAPTER 6
Interrelationship of Purine and Pyrimidine Metabolism. M. TATIBANA. With 3 Figures
A. Introduction 125
B. Control of Enzyme Activity by Pyrimidines in Purine Biosynthetic
Pathways . . . . . . . . . . . . . . . . . . . 125
I. Phosphoribosyl Pyrophosphate Amidotransferase 125
II. Adenylosuccinate Synthetase 126
III. IMP Dehydrogenase . . . . . . . . . . . . 126
IV. Adenosine Kinase ............. 126
C. Control of Enzyme Activity by Purines in Pyrimidine Biosynthetic
Pathways. . . . . . . . . . . . . . . . . . . . . . . . . 126
x
Table of Contents
I. Carbamoyl-Phosphate Synthetase II 127
II. Aspartate Carbamoyltransferase 130
III. Oro tate Phosphoribosyltransferase 130
IV. Orotidylate Decarboxylase 131
V. Cytidine Triphosphate Synthetase 131
VI. Uridine-Cytidine Kinase 132
D. Regulation of the Ribonucleotide System 132
E. Disorders in Nucleotide Biosynthesis Induced by Exogenous Purines and
Pyrimidines . . . . . . . . . . . . . . . . . . . . . . 133
I. Disorders in Purine Biosynthesis Induced by Orotate 133
II. Inhibition of Pyrimidine Nucleotide Synthesis by Adenine 134
III. Interference of Adenosine and Other Purine Nucleosides with
Pyrimidine Biosynthesis . . . . . . . . . . . . . . . . 135
IV. Effects of Allopurinol on Pyrimidine Biosynthesis De Novo 138
F. Role of Cellular Levels of Phosphoribosyl Pyrophosphate in Coordinate
Control of Purine and Pyrimidine Nucleotide Biosynthesis . . . . . . . 140
G. Possible Interrelationship Between Catabolism of Purine and Pyrimidine
N ucleotides . . . . . . . . . . . . . . . . . . . . . . . . 144
I. Dephosphorylation of Purine and Pyrimidine Mononucleotides 144
II. Cleavage of Glycosidic Bond . . . . . . . . . . . . . 146
H. Possible Interference Between Purine and Pyrimidine Transport 146
I. Conclusion 147
References . 148
CHAPTER 7
Abnormalities of PRPP Metabolism Leading to an Overproduction of Uric Acid.
M.A. BECKER. With 3 Figures
A. Introduction ..... 155
B. Metabolism of PRPP . . 155
I. Utilization of PRPP 155
II. Intracellular PRPP Concentration 158
III. Determinants of PRPP Synthesis 158
1. PRPP Synthetase 158
2. Substrates 159
3. Inhibitors 161
4. Activators 163
5. Structure and Activity of PRPP Synthetase 164
6. Control of the Amount of PRPP Synthetase 165
C. PRPP Availability and the Rate of Purine Synthesis De Novo. 165
I. Studies of Amidophosphoribosyltransferase and Its Effectors 166
II. Effects of Pharmacologic Agents on PRPP Concentration and Purine
Synthetic Rate . . . . . . . . . . . . . . . . . . . . . 166
D. Studies of PRPP Metabolism in Uric Acid Overproducers Without
Recognized Enzyme Defects . . . . . . . . . . . . . . . . . 167
Table of Contents XI
E. PRPP Metabolism in Enzyme Defects Associated with Uric Acid Over-
production .............. 169
I. Increased PRPP Production . . . . . 169
1. Excessive PRPP Synthetase Activity 170
2. Glucose-6-phosphatase Deficiency 173
3. Increased Glutathione Reductase Activity 174
II. Decreased PRPP Use . 174
1. HGPRT Deficiency ......... 175
2. APRT Deficiency ......... 176
3. Purine Nucleoside Phosphorylase Deficiency 177
References 178
Biochemistry and PhysiolQgy of Uric Acid: Renal Disposal
CHAPTER 8
Urate Excretion in Nonmammalian Vertebrates. W. H. DANTZLER. With 2 Figures
A. Introduction ......................... . 185
B. Occurrence of Urates as the Primary Excretory Products of Nitrogen
Metabolism . . . . . . . . . . . . . 185
C. The Process of Renal Excretion of U rates 188
I. Filtration at the Glomerulus . . . . 188
II. Transport by the Renal Tubules 189
1. Direction of Net Urate Transport 189
2. Sites of Tubular Transport 191
3. Process of Tubular Transport 192
4. Specificity of Tubular Transport 198
D. Chemical Forms of Urates in Urine . 200
I. Forms in Liquid Phase of Urine · 200
II. Forms in Urine Precipitates · 202
III. Modification of Form and Ionic Content of Urates by Transport
Processes in Bladder or Cloaca · 205
E. Concluding Remarks · 206
References · 207
CHAPTER 9
Urinary Excretion of Uric Acid in Nonhuman Mammalian Species.
F. ROCH-RAMEL and G. PETERS
A. Introduction ..... · 211
B. Methods of Investigation 212
I. Clearance Methods 213
II. Stop-flow Analysis . 213
XII Table of Contents
III. The Double-Isotope-Precession Method . 213
IV. Micropuncture Methods ...... . 213
1. Microinjection Technique . . . . . 213
2. Microperfusion of Tubular Segments In Vivo 214
3. Microperfusion of Isolated Tubular Segments from Rabbits In Vitro 214
4. Free-flow Micropuncture . . . . . . . . . . . . . . . . . . 214
5. Uptake of Uric Acid by Renal Tissue . . . . . . . . . . . . . 214
V. Analytic Methods Used for Measuring Urate Concentrations in Body
Fluids ........................... 215
VI. Overall Renal Function and Plasma Concentrations of Uric Acid in
Various Mammalian Species 215
C. Rabbit .......... . 215
I. Ultrafilterability of Urate 217
II. Fractional Excretion of Urate 217
III. Micropuncture Studies and Microperfusion of Isolated Tubular
Segments ............... . · 219
IV. Uptake of Urate into Renal Cortical Tissue In Vitro · 219
V. Drug Effects .220
VI. Conclusion ................ . 222
D. Dog ..................... . 222
I. Comparison of Dalmatian and Non-Dalmatian Dogs 222
II. Effects of Drugs 226
III. Conclusion ................. . 226
E. Rat ...................... . 226
I. Plasma Concentration and Ultrafilterability of Urate 226
II. Fractional Excretion of Urate ......... . 228
III. Site and Nature of Transtubular Movements of Urate 230
1. Proximal Convoluted Tubules 230
2. Henle's Loops . . . . . . 233
3. Distal Convoluted Tubules 233
4. Collecting Ducts . . . . 233
IV. Effects of Drugs . . . . . 234
V. Experimental Hyperuricemia 236
VI. Conclusion 237
F. Mouse · 237
G. Guinea Pig 237
H. Pig .... 239
J. Nonhuman Primates 239
I. Old-World Monkeys 240
II. New-World Monkeys · 240
1. Effects of Drugs and Metabolites · 241
III. Apes . . . . . . . . . . . . . · 243
IV. Conclusion ......... . 243
K. Isolated Data on Other Species of Mammals 243
L. Conclusions 245
References . . · 247
Description:Uric acid has attracted the attention of scientists from a broad spectrum of disciplines, and in recent years dramatic progress has occurred within many of these disciplines. This volume is designed to fill void in the field. Major works in the past five years have provided comprehensive reviews of
