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Disorders of Purine and Pyrimidine Metabolism
Abstract
During the past year, a number of developments have increased substantially our understanding of the coordinated relationship of human purine and pyrimidine metabolism and the role of specific aberrations of metabolism in this area in causation of human disease. However, in order to understand and appreciate the significance of these developments, background information is required. Since the subject has not previously been reviewed in this series, the considerable material relating clinical and biochemical correlations needs to be presented. A comprehensive description with specific citations of all major contributions of even the recent years is not possible within the space limitations of this chapter. Therefore, the information will be summarized largely by referencing more comprehensive reviews and more recent reports, rather than crediting, in all cases, the original citations of the various observations.
... Other causes to consider in the absence of clinical or laboratory evidence of malignancies are dehydration, lactic acidosis, starvation, diuretic therapies, or renal diseases. 8,9 Typically, when I see elevated uric acid, I am concerned about a malignant process. I obtain lactate dehydrogenase, erythrocyte sedimentation rate, and further evaluations based on clinical scenarios. ...
A 17-year-old girl presented with facial swelling and shortness of breath to an outside emergency department. She was treated for an allergic reaction with steroids and antihistamines, and discharged from the hospital. Subsequently, she was referred as an outpatient to pediatric nephrology for recurrent edema and proteinuria. Initial laboratory workup by nephrology was significant for a normal complete blood count and reassuring electrolyte panel. Pertinent laboratories were a creatinine of 0.5 mg/dL (0.4-1.1 mg/dL) and an albumin 2.3 g/dL (3.5-5.0 g/dL). The urine protein-to-creatinine ratio was >7 (<0.2). A renal ultrasound showed symmetrically sized kidneys with normal echotexture. The patient's renal biopsy results were consistent with minimal change disease. Based on the biopsy results, prednisone was started. Due to a poor response to prednisone, an alternate immunomodulator therapy was selected. Her subsequent complete blood counts showed a downward trend of all cell lines and an elevated serum uric acid. Concurrently, she reported worsening fatigue, low back pain, nausea, vomiting, night sweats, and pruritus. More details of her case and the outcome are presented.
... This seems not to be the case in erythrocytes which lacks a metabolic system of protein synthesis. However, erythrocytes transfer adenosine from the liver to periphery (Seegmiller, 1978), and elevated ATP level in erythrocytes can be a consequence of increasing the adenosine turnover necessary for put-me supply into regenerating epidermis. The question of interest is constancy of the EC in erythrocytes. ...
1. Adenine nucleotide concentrations and metabolism in red blood cells (RBC) and RBC ghosts from psoriatic patients and healthy subjects were compared. 2. The ATP and total adenine nucleotide levels and the adenylate energy charge (EC) were elevated in the blood from psoriatic patients. 3. The rate of glycolytic production of ATP by intact RBC was unchanged, but the Na+, K(+)-ATPase activity of RBC ghosts was decreased significantly in psoriasis. 4. Results suggest that the defect in adenine nucleotide metabolism is a systemic manifestation of psoriasis, and that the quantification of adenine nucleotides in RBC and in whole blood samples may be of pathophysiological value in psoriatic lesion.
The field of urinary stone disease can conveniently be divided into those diseases that clearly result from excessive supersaturation of the urine for the offending crystalline species and those that do not. Recent developments in the former area are mainly confined to describing new disorders or improving therapy; there is little debate on pathogenesis and hardly a reference to physical chemistry. For calcium stone disease, the situation is quite different. Not only is excessive supersaturation for calcium oxalate often difficult to demonstrate, but normals may have crystalluria. The lofty realms of complex physical chemistry are increasingly invoked. Further, in contrast to other stone diseases, the contribution of diet to both the cause and treatment of calcium stone disease must be considered. It is this disease entity that presents the greatest continuing challenge.
Background:
Seafood is regarded as a high purine food that may induce gout, which has attracted extensive attentions about its safety. Therefore, the aim of this study was to develop a simple and reliable method to determine the purine content in seafood and its changing rules during storage to guide consumers with referenced content at different freshness.
Results:
Chromatographic separation was carried out using Waters Atlantis dC18 column, and potassium phosphate monobasic solution (0.02 mol/L, pH=3.6) as a mobile phase. The average recovery yields of 4 purines were 91.5 % ~ 105.0 %, and RSD values were around 1.8 % ~ 6.5 %. Shrimp and snail contained higher amounts of purine than fish and bivalve; the livers and skins of fish contained higher amounts of purine than muscles; and main purine varied depending on the type of seafood. Besides, purine content of seafood was changing during storage.
Conclusion:
The purine content of seafood was different depending on species, body parts and fresh degrees, which could recommend consumers a healthy diet, especially for people with hyperuricemia and gout.
Galton’s and Mendel’s Paradigm: Gene Action Is Well Understood. The discussion of the twin method has shown the possibilities, but still more clearly the limitations of genetic analysis involving comparison of phenotypes without reference to the action of single genes. The twin method is an extension of the paradigm created by F. Galton when he measured and compared quantitatively varying characters in close relatives. Heritability estimates whether based on twins or on family data indicate an underlying genetic variability in the population but do not provide any information as to the mechanisms of this variability. They pose questions but do not answer them.
The biomedical sciences have been remarkably successful in dealing with exogenously originating pathologies such as infectious diseases. This success, however, has uncovered a more formidable opponent of health and general well being, the intrinsically originating pathologies. These are the disabling or degenerative diseases, which are generally described as being caused by or related to the aging processes. The vast number of human diseases which have an intrinsic origin is just becoming appreciated, and the studies of these dysfunctions and the methods to be developed for their treatment are predicted to occupy the future efforts of much of the biomedical sciences (Ludwig, 1980).
Gene Action and Genetic Strategies. How do genes manage to determine the development and function of the organism? This is the basic problem of genetic biology that should be solved. The topics discussed earlier such as the structure of the genetic material and Mendelian segregation are interesting scientifically because they help in solving this basic question. In Chap.6 Mendelism is described as the central paradigm of genetics. Thus, a Mendelian mode of inheritance for a certain phenotype points to a specific change within the information-carrying DNA, and the study of linkage with DNA variants as markers leads to precise localization of the gene causing this phenotype. After the nature of the genetic alteration has been defined, the path of gene action between genotype and phenotype can be elucidated. For a long time linkage studies were known in principle to be the “King’s road” leading to gene localization. Linkage study in humans is more difficult than in experimental organisms because of the lack of directed matings. Although statistical techniques needed for human gene mapping have been available for some time, practical implementation was impeded by the lack of suitable genetic markers that could be used as landmarks for gene localization. This has fundamentally changed with discovery of the very frequent DNA polymorphisms. (Sect.12.1.2).
This study was carried out to investigate novel cardioprotective effects of urea and the underlying mechanisms. The cardiac functions under oxidative stress were evaluated using Langendorff perfused isolated heart.
Isolated dogfish shark hearts tolerated the oxidative stress generated by electrolysis (10 mA, 1 min) of the perfusion solution (n=4), and also showed normal cardiac functions during post-ischaemia reperfusion (n=4). The high concentration of urea (350 mM) in the heart perfusate was indispensable for maintaining the normal cardiac functions of the shark heart.
Urea at 3–300 mM (n=4 for each group) protected the isolated rat heart against both electrolysis-induced heart damage and post-ischaemia reperfusion-induced cardiac injury.
A concentration-dependent scavenging effect of urea (3–300 mM, n=4 for each group) against electrolysis-induced reactive oxygen species was also demonstrated in vitro.
Urea derivatives as hydroxyurea, dimethylurea, and thiourea had antioxidant cardioprotective effect against the electrolysis-induced cardiac dysfunction of rat heart, but were not as effective as urea in suppressing the post-ischaemia reperfusion injury.
Our results suggest that urea and its derivatives are potential antioxidant cardioprotective agents against oxidative stress-induced myocardium damage including the post-ischaemia reperfusion-induced injury.
British Journal of Pharmacology (1999) 128, 1477–1484; doi:10.1038/sj.bjp.0702944
The most severe, and also a relatively common immunodeficiency syndrome involves both antibody- and cell-mediated immune mechanisms. In more modern terms the ‘severe combined immunodeficiency’ syndromes (SCID) are defined as all diseases resulting from marked and longlasting functional impairment of both the T- and B-cell system. Accordingly, the clinical symptoms and signs involve many organs and invariably lead to death. An almost constant feature is thymic dysplasia.
In the past decade extensive research has been addressed to inducing, selecting, and analyzing specific heritable phenotypic alterations of mammalian cells in culture. The vast literature which has resulted from these efforts has been reviewed on several occasions. The earlier monographs of the nascent discipline could be encyclopedic (De Mars 1971; Thompson and Baker 1973), while some of the more recent treatments ofmammalian cell genetics have been highly specialized and even analytic (e.g. Siminovitch 1976; Basilico 1977; Bakerand Ling1978).Here we will attempt to mark entrance into the “second generation” of somatic cell genetics as characterized by a number of gene transfer techniques and also emphasize very limited specific areas that have not been rigorously discussed previously.
1.1. The concentration of PRPP and the activities of PRPP synthetase, OPRT, ODC, HPRT and APRT have been determined in lymphocyte extracts of man, cattle, horse, pig and sheep.2.2. PRPP concentration and PRPP synthetase activity were similar in all species.3.3. OPRT and ODC activities were very low in equine lymphocytes and relatively high in porcine lymphocytes.4.4. OPRT and ODC activities were coordinate in all species studied.5.5. HPRT activity was higher in equine lymphocytes than in those of the other species. HPRT activity was higher than APRT activity in all animal species studied.6.6. APRT activity was similar in equine and human lymphocytes and very low in those of sheep, cattle and pig.
This paper presents epidemiological data on the prevalence of 26 common (i.e., having a lifetime prevalence of more than 1 per 104 individuals in the population) multifactorial diseases in Hungary and estimates of detriment associated with them. The detriment is expressed using 3 indicators, namely years of lost life (LL), potentially impaired life (PIL) and actually impaired life (AIL). The total prevalence of these diseases in Hungary has been estimated to be about 6500 per 104 individuals in the population. This estimate is in agreement with published data for other parts of the world. On the basis of clinical severity, these diseases have been split into 3 groups, namely (1) very severe (schizophrenia, multiple sclerosis, epilepsy, acute myocardial infarction and related conditions, and systemic lupus erythematosus); (2) moderately severe and/or episodal or seasonal (15 entities including Graves' disease, diabetes mellitus, gout, affective psychoses, essential hypertension, peptic ulcers, asthma, etc.); and (3) less severe than those in the first 2 groups (varicose veins, allergic rhinitis, atopic dermatitis, Scheuermann disease and adolescent idiopathic scoliosis). The essential clinical and genetic aspects of these diseases are briefly discussed. With the exception of epilepsy, none of the diseases included in our list causes mortality between ages 0 and 19. However, they are among the leading causes of death between ages 20 and 69 and thereafter. A sizeable proportion of those with essential hypertension, diabetes mellitus, rheumatoid arthritis, etc. survive to 70 years and beyond, as do those with gout, glaucoma, allergic rhinitis, psoriasis, etc. Overall, about 16% of all deaths that occur in Hungary every year (all age groups) can be attributed to these diseases.
Humans have the longest maximum lifespan potential of any mammalian species and also appear to consume more energy over this lifespan on a per-weight basis than any other species (Cutler, 1984a). These two unique biological characteristics of humans are the result of an unusually slow aging rate.
Low serum cholesterol concentrations are associated with deaths from cancer. This association was found in a prospective study of middle aged men in Malmö and consideration of possible explanations for the lowering of serum cholesterol prompted an analysis of serum urate in relation to deaths from cancer. A total of 127 of the 7725 participants in the Malmö study had died since screening. A weakly positive but significant correlation between raised serum urate concentration and total mortality was found. This correlation was wholly explained by neoplastic deaths (p less than 0.01), while there were no associations with alcohol related deaths or with deaths from coronary heart disease. When the deaths from cancer were classified as "early" or "late"--that is, occurring less than or more than 2.5 years after the screening--the correlation between raised urate concentrations and cancer mortality was confined to the "early" deaths (p less than 0.001). Further studies are needed to substantiate the relation between raised serum urate concentrations and fatal neoplasia. Nevertheless, these findings weigh against recent suggestions that uric acid has an antioxidant protective effect against cancer.
Urate has been shown to be a major antioxidant in human serum and was postulated to have a biological role in protecting tissues against the toxic effects of oxygen radicals and in determining the longevity of primates. This possibility has been tested by determining if the maximum lifespan potentials of 22 primate and 17 non-primate mammalian species are positively correlated with the concentration of urate in serum and brain per specific metabolic rate. This analysis is based on the concept that the degree of protection a tissue has against oxygen radicals is proportional to antioxidant concentration per rate of oxygen metabolism of that tissue. Ascorbate, another potentially important antioxidant in determining longevity of mammalian species, was also investigated using this method. The results show a highly significant positive correlation of maximum lifespan potential with the concentration of urate in serum and brain per specific metabolic rate. No significant correlation was found for ascorbate. These results support the hypothesis that urate is biologically active as an antioxidant and is involved in determining the longevity of primate species, particularly for humans and the great apes. Ascorbate appears to have played little or no role as a longevity determinant in mammalian species.
Adenosine and deoxyadenosine are known inhibitors of the in vitro proliferative response of peripheral blood lymphocytes(PBL) to various mitogens(1–7). Erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride (EHNA), an inhibitor of the enzyme adenosine deaminase(ADA), potentiates the inhibitory effects of both adenosine and deoxyadenosine. The incorporation of3H-leucirie into protein appeared to be a more sensitive index of adenosine toxicity than the incorporation of3H-thymidine(1). A differential sensitivity of cultured human T and B lymphoblasts towards the toxic effects of adenosine and deoxyadenosine has been observed: T cells are more sensitive than B cells(8,9). On the basis of3H-thymidine incorporation, mouse splenic cells stimulated by lipopolysaccharide(LPS) were less sensitive to the addition of adenosine than the concanavalin A(ConA) stimulated cells (10). Using a plaque forming cell assay, a biphasic effect of adenosine was seen on the in vitro antibody production in mice; concentrations of adenosine around 1mM stimulated antibody production in vitro, whereas concentrations above 1.5 mM had inhibitory effects (10).
The association between serum uric acid level and risk of coronary heart disease (CHD) over 21 years was investigated among 6411 middle-aged Japanese-American men who were participants in the Honolulu Heart Program. In an age-stratified Cox regression model, high serum uric acid (quartile 4 [>6.7 mg/dl], relative to quartile 1 [<5.0 mg/dl]) was a significant predictor of definite CHD (RR = 1.33; 95% confidence interval = 1.08-1.63; p = 0.006). However, when adjustment for confounders (body mass index, heavy alcohol consumption, triglycerides, diastolic blood pressure, blood glucose, and the ratio of animal to vegetable protein) was made, the association of high uric acid with coronary events was substantially reduced and became nonsignificant (RR = 1.14; 95% confidence interval = 0.92-1.42; p = 0.21). There was a significant interaction between serum uric acid and drinking status (P = 0.03). Thus, the risk of definite CHD associated with high urate levels (quartile 4), relative to low levels (quartile 1), was elevated in the abstainers (RR = 1.40; 95% confidence interval = 1.01-1.93; p = 0.02), but not in light and moderate drinkers (RR = 1.1 1; 95% confidence interval = 0.79-1.55; p = 0.58) or among the heavy drinkers (>40 ml of ethanol/day; RR = 0.57; 95% confidence interval = 0.27-1.21; p = 0.08). It is concluded that elevated uric acid may be associated with higher CHD among alcohol abstainers. Whether raised urate is an etiological factor for CHD or a manifestation of existing arterial disease in nondrinkers deserves further investigation.
Hypoxanthine-guanine phosphoribosyltransferase from Chinese hamster brain, liver, and V79 tissue culture cells appears to have identical structural and catalytic properties. The enzyme has been purified 540-fold to apparent homogeneity from Chinese hamster brain. The native molecular weight is 78,000 to 85,000 determined by Sephadex G-100 column chromatography and acrylamide gel electrophoresis. The enzyme appears to consist of three subunits of molecular weight 25,000 determined by sodium dodecyl sulfate acrylamide gel electrophoresis. Electrofocusing and acrylamide gel electrophoresis demonstrate the presence of at least three isozymes. The enzyme is remarkably stable at 85° if first incubated in 1 mm 5-phosphoribosyl 1-pyrophosphate. The enzyme is active from pH 5.5 to 11 with maximum activity at pH 10. The enzyme displays Michaelis-Menten kinetics with apparent Michaelis constants for hypoxanthine, guanine, and phosphoribosylpyrophosphate of 0.52, 1.1, and 5.3 µm, respectively.
The potency of inhibition of deoxyadenosine kinase by nucleotides of cytosine is dependent on the nature of the pentose moiety (deoxyribose > arabinose > ribose). Kinetic data suggest that deoxyadenosine (dAdo), deoxyguanosine (dGuo), and cytidine (Cyd) are substrates for dAdo kinase. The apparent Km values for these phosphate acceptors are: dAdo (0.7 mm), dGuo (1.1 mm), and Cyd (0.6 mm). The inhibition of deoxyadenosine kinase by dATP, dGTP, and dCTP appears to be noncompetitive with the phosphate acceptor and competitive with the phosphate donor (ATP). Kinetic analysis indicates that the reaction catalyzed by deoxyadenosine kinase follows a "ping pong" mechanism.
Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) has been purified to homogeneity from human erythrocytes obtained
from one male donor. The normal human enzyme has a Stokes radius of 36 A with a molecular weight of 68,000 and is composed
of two subunits which have identical molecular weight and net charge.
Three isoenzymes were reproducibly distinguished by preparative isoelectric focusing. This electrophoretic heterogeneity appears
to result from a nongenetic, post-transcriptional alteration of one or both subunits.
In recent years, a growing interest has prompted increasing numbers of research publications and scientific conferences on the subject of urolithiasis. The aims of this symposium were three: a) to review and inte grate recent progress in major subject areas, b) to discuss current research developments and c) to stimulate interchange between investigators in Europe and in America. In a series of morning lectures, invited, recognized experts presented comprehensive reviews of major fields of urolithiasis research such as the physical chemistry of crystal formation, the metabolism of stone forming substances, and modes of therapy. A special emphasis was given to general renal physiology and the renal excretion of Ca++, Pi, Mg, oxalate and urate. Despite its obvious importance, renal function has been relatively neglected in uro lithiasis research. New research results were presented by the mechanism of after noon poster sessions. This procedure permitted informal lengthy discussions between those participants especially interested and the responsible investigator himself. In addition, informal group discussions were organized during the evenings on an ad hoc basis. In this volume, both the review lectures and brief summaries of the poster presentations have been collected. Interchange between European and American investigators was achieved by the direct participation of a large delegation from North America. This large attendance was made possible by the generous support of the National Institute for Arthritis, Metabolism and Digestive Disease U.S. N.I.H.
Over the past two decades a number of attempts have been made, with varying degrees of success, to collect in a single treatise available information on the basic and applied pharmacology and biochemical mechanism of action of antineoplastic and immunosuppressive agents. The logarithmic growth of knowledge in this field has made it progressively more difficult to do justice to all aspects of this topic, and it is possible that the present handbook, more than four years in preparation, may be the last attempt to survey in a. single volume the entire field of drugs em ployed in cancer chemotherapy and immunosuppression. Even in the present instance, it has proved necessary for practical reasons to publish the material in two parts, although the plan of the work constitutes, at least in the editors' view, a single integrated treatment of this research area. A number of factors have contributed to the continuous expansion of research in the areas of cancer chemotherapy and immunosuppression. Active compounds have been emerging at ever-increasing rates from experimental tumor screening systems maintained by a variety of private and governmental laboratories through out the world. At the molecular level, knowledge of the modes of action of estab lished agents has continued to expand, and has permitted rational drug design to playa significantly greater role in a process which, in its early years, depended almost completely upon empirical and fortuitous observations.
The deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a very rare hereditary disorder causing excessive purine production (1). When the enzyme deficiency is virtually complete it causes the pediatric neurological LeschNyhan syndrome (LNS); when partial, it causes severe gout and uric acid lithiasis. In most purine overproducers, including the HGPRT deficient patients, the pathology caused by the excessive amounts of uric acid is avoided successfully by the treatment with the xanthine oxidase inhibitor allopurinol, which effectively reduces uric acid levels. In overproducers with normal HGPRT activity, allopurinol administration is associated also with a significant deceleration of purine synthesis, manifest in a marked reduction in the amount of total purines excreted. In HGPRT deficiency this effect does not occur and the amount of the excreted oxypurines, replacing the uric acid, is markedly increased, rendering such patients to be at risk for xanthine stone formation. Xanthine lithiasis was indeed documented in allopurinol-treated children with the complete enzyme deficiency (2-4). The following is the first case of xanthine stones formation in an allopurinol-treated gouty patient with partial HGPRT deficiency (5).
The Anturane Reinfarction Trial is a randomized, double blind, multicenter clinical trial comparing sulfinpyrazone (200 mg four times a day) and placebo in the prevention of cardiac mortality among patients with a recent documented myocardial infarction. Results represent data accumulated on 1475 eligible patients entered 2 to 35 days after myocardial infarction and followed for an average of 8.4 mth. The data reflect excellent randomization, compliance with therapy and tolerance of the drug. All 69 deaths were of a cardiovascular nature (68 cardiac and one cerebrovascular). For cardiac deaths, the annual death rate was 9.5% in the placebo group and 4.9% in the sulfinpyrazone group, representing an observed reduction of 48.5% (P=0.018). The annual sudden-cardiac-death rate was 6.3% for the placebo and 2.7% for the sulfinpyrazone group, representing a 57.2% reduction in sudden-cardiac-death rate P equals 0.015). Sulfinpyrazone appears to be effective in reducing cardiac deaths during the first year after myocardial infarction.
The origin of the histological lesion in gout has frequently been disputed. Conflicting views are discussed and compared with studies in which we have demonstrated: 1. That intratubular crystals can become interstitial with the eventual production of a chronic interstitial nephritis indistinguishable from that previously attributed to the interstitial deposition of sodium urate. 2. The existence of a distinct subgroup of gouty patients with a specific renal lesion occurring in young subjects characterized by a pronounced inability to concentrate the urine, in the absence of hypertension. 3. A form of crystalluria hitherto misdiagnosed as 'uric acid', 2,8-dihydroxyadenine-crystalluria, which can produce urolithiasis and subsequent nephropathy.
In 1972, Giblett and co-workers1 and Dissing and Knudsen2 reported the coexistence of adenosine deaminase (ADA) deficiency and severe combined immunodeficiency disease (SCID). The discovery of an association between deficiency of an enzyme and an immunodeficiency represents a major conceptual landmark in that we now recognize that at least some immunodeficiency diseases, ‘experiments of nature’ as Dr Robert A. Good so elegantly called them, may indeed be inborn errors of metabolism’ whose major consequences are manifest in the function of the immune system3. Therefore, if some immunodeficiencies are indeed metabolic diseases, the diagnostic and therapeutic approaches to these disorders must be similar to our approach to metabolic diseases, namely biochemical and pharmacological. Rational approaches to therapy presupposes an understanding of the biochemical basis of the immune dysfunction. This paper describes some of our investigations into the adenosine deaminasedeficient form of severe combined immunodeficiency disease, as well as our experience with enzyme replacement therapy for this disorder and some recent studies with pharmacological agents upon adenosine deaminase-deficient lymphocytes.
Abundant evidence has been presented in recent years indicating an important role for the intracellular concentration of 5-phosphoribosyl 1-pyrophosphate (PRPP)1 in the regulation of the rate of purine nucleotide synthesis de novo. Extensive investigations of the effects of pharmacologic and genetic alterations in PRPP metabolism on human purine synthesis have been major sources of this evidence. In the present chapter, the metabolism of PRPP will be reviewed and particular emphasis will be given to determinants of PRPP synthesis and to genetically determined biochemical aberrations in which increased availability of PRPP leads to excessive purine nucleotide synthesis and thus uric acid overproduction in man.
The inborn errors of metabolism have played a special role in the development of human genetics as a scientific discipline. The study of these disorders, each of them individually uncommon, has pointed out the ways in which molecular expression of gene action takes place in man. It has given us new understanding of mechanisms of human variation. It has pioneered in the field of prenatal diagnosis and has permitted new approaches to questions of population genetics by permitting the detection of recessive genes in heterozygotes. Each of these aspects of modern biochemical genetics is exemplified by the inborn errors of purine metabolism, an area in which there have been exciting new developments.
Administration of allopurinol or its major metabolic oxidation product, oxipurinol, to man consistently results in inhibition not only of uric acid synthesis but also of pyrimidine synthesis. Molecular correlates of the latter inhibition produced by oxipurinol have been studied in permanent human lymphoblast lines in tissue culture, which appear to be satisfactory models for the study of this drug effect. Incubation of intact lymphoblasts with oxipurinol resulted within 90 min in significant inhibition of incorporation of [14C]orotic acid but not [3H]uridine into cold acid precipitable counts. This inhibition of pyrimidine synthesis was correlated with the generation of an orotidylic acid decarboxylase inhibitor which, in cell free extracts, required 5 phosphoribosyl 1 pyrophosphate and oxipurinol for its formation and could be generated in extracts of cells deficient in hypoxanthine guanine phosphoribosyltransferase. Stabilization of both orotidylic acid decarboxylase and orotate phosphoribosyltransferase also resulted from incubation of lymphoblasts with oxipurinol. Production of the stabilized activities appeared to coincide temporally, in substrate requirements, and in reversibility with the generation of the inhibitor of orotidylic acid decarboxylase activity, suggesting a common molecular basis for these effects. In addition oxipurinol treatment resulted in an alteration in the quaternary structure of the bifunctional enzyme complex containing both activities, with an increase in molecular weight from 41,000 to 108,000 as estimated by gel filtration studies. In the higher molecular weight material both increased stability and inhibition of orotidylic acid decarboxylase were demonstrated. These findings are in accord with the suggestion that ribonucleotides of oxipurinol result in inhibition of pyrimidine synthesis through alterations in the activity, stability, and quaternary structure of the enzyme complex. A concentration dependent increase in the specific activities of orotidylic acid decarboxylase and orotate phosphoribosyltransferase has been demonstrated in both lymphoblasts and fibroblasts incubated with oxipurinol. In lymphoblasts this increase in enzyme activity occurred within 2 to 3 hr and was not prevented by treatment of the cells with cycloheximide. Stabilization of the enzymes during extraction from the cell or direct activation of the enzyme activities appear to be more likely explanations for the increased enzyme activities than induction of new enzyme synthesis of inhibition of normal enzyme catabolism. No differences were found between normal and hypoxanthine guanine phosphoribosyltransferase deficient lymphoblast (or fibroblast) lines in activities of either orotate phosphoribosyltransferase or orotidylic acid decarboxylase.
A patient in whom avascular necrosis of one femoral head and, later, clinical gout developed underwent hip surgery which revealed that the femoral head and surrounding synovial membrane were covered with monosodium urate crystals. Although cases of hyperuricemia and gout in nontraumatic avascular necrosis of the femoral head have been reported, examination of biopsy specimens from such patients has been rare. Careful studies will be necessary to determine the incidence and importance of urate crystal deposition in such patients.
In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide.Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily. Whereas the serum uric acid level rose moderately in the hydrochlorothiazide-treated patients, it fell strikingly to less than half of the pretreatment level in patients treated with ticrynafen. Body weight decreased slightly in both groups, as did serum potassium levels. Blood urea nitrogen and serum creatinine levels rose slightly in both groups. The magnitude of these changes was not significantly different between the two groups. Use of ticrynafen was well tolerated.Ticrynafen appears to be a useful new antihypertensive agent because of its unique combination of diuretic, antihypertensive, and hypouricemic effects.(JAMA 237:652-657, 1977)
BONE metastases are common in bronchogenic carcinoma, but the occurrence of metastases to small bones of the hands and feet is relatively rare.1 It is particularly unusual for such metastases to be responsible for the presenting complaint of a patient with lung cancer. We recently encountered two patients with squamous cell carcinoma of the lung; one had symptoms referrable to such peripheral bone metastases, and one had symptoms simulating gout.Report of Cases
Case 1. —
A 52-year-old man was admitted to the hospital with a two-month history of painful swelling of his right ring finger. For several weeks he had experienced intermittent fever and chills. He had experienced a chronic cough and dyspnea during exertion for a number of years. He had smoked three packs of cigarettes per day for 35 years and had traveled extensively, including a visit to parts of southwestern United States within the past
Arterial disease is respected as an inevitable as well as the most serious complication of gout. Barring accident or other common hazards, the patient afflicted with gout will die directly or indirectly of changes in his circulatory apparatus. Formerly, gouty lesions were ascribed to arterial changes; this opinion is no longer held. Hyperuricemia is not believed to be the cause of the vascular changes. Instead, the underlying, unknown cause of the other manifestations of gout is thought to induce the arteriosclerosis.Discovery of urate in the arteries or in the heart adds specificity to the cardiovascular changes. Urate crystals in blood vessels or in the heart were reported by the earliest writers. The authenticity of these reports has been doubted, notably by Minkowski. Deposition of urates in the vessel walls and in the heart valves is regarded not as the cause of the tissue changes but rather as an accompaniment
A female patient, at the moment 2½ years old, with a purine nucleoside phosphorylase (PNP) deficiency showed a gradual decrease of T cell immunity during the first year of life whereas B cell immunity developed normally (1) Later on in life some disturbance of B cell immunity also developed as could be concluded from the appearance of homogeneous immunoglobulins in the serum from the decrease in the synthesis of specific antibodies. Earlier studies (1, 2) have shown that an inherited PNP deficiency existed in two older sisters of the patient, both suffered from the same immunodeficiency and have died. The oldest sister has been treated with several thymus transplants, resulting in a partial and transient restoration of T cell function. However the most obvious therapeutic approach of these patients would be correction of the consequences of the metabolic defect. Therefore, the patient under study was treated by oral substitution with uridine and purines and afterwards with several transfusions of irradiated red cells and plasma. The former treatment was rather unsuccessfull, the latter resulted in a remarkable change in the metabolic state of the patient and some improvement of in vicro immune functions. In contrast to findings of Polmar et al. (3) in a ADA deficient patient, complete immunological restoration could not be Achieved by this treatment until now.
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Radiological and morphological findings in advanced arthritis urica and pyrophosphate arthropathy are well known. In contrast, the early changes of synovial membrane in these disturbances of metabolism pose diagnostic problems. With the assistance of various cytological techniques and polarizing microscopical as well as electron microscopical investigation it was examined to what extent needle biopsies can be helpful in the differential diagnosis of gout and pseudogout.
Four cases of the Lesch Nyhan syndrome found in the Tokyo area were given L 5 hydroxytryptophan orally. L 5 hydroxy tryptophan relieved self mutilation effectively without causing any side effects. However this substance did not alleviate choreoathetoid movement. Self destructive behavior may be caused by an imbalance of cerebral amines, especially of serotonin.
Adenosine deaminase (ADA) deficiency is associated with a form of severe combined immunodeficiency disease (SCID). Enzyme replacement therapy has restored immunologic competence in some ADA-SCID patients (Polmar et al. N Engl J Med 295:1337, 1976). Their lymphocytes, however, remain ADA deficient. Enzyme therapy also reduces the high levels of deoxyATP (dATP) present in these patients prior to therapy. The effects of adenosine and deoxyadenosine upon proliferation of ADA deficient lymphocytes were studied using 3H-leucine incorporation as a measure of cell proliferation. Studies were carried out upon lymphocytes from one ADA-SCID patient and three normal individuals whose lymphocytes were made ADA deficient with the ADA inhibitor EHNA.
Patients with combined immunodeficiency (CID) and adenosine deaminase (ADA) deficiency may have low or absent ADA activity in various tissues. Hirschhorn et al. have shown that the activity in patient fibroblasts is a mutant form of ADA (PNAS 73: 213, 1976). Others have suggested that the deficiency reflects an inhibition of ADA (Trotta et al., PNAS 73: 104, 1976). We have isolated and in part characterized properties of the residual ADA from spleen of one patient. Radioimmunoassay for ADA protein in erythrocytes and spleen extracts of the patient showed no cross-reacting protein. Chromatography of ADA-CID spleen extracts produced a fraction with adenosine deaminating activity which could not be adsorbed on affinity or anti-ADA columns. The deaminating activity could not be inhibited with erythro-9-(2-hydroxyl-3-nonyl) adenosine. The pH optimum activity curve and Km differed from normal spleen ADA. A similar fraction, representing about 1% of the total ADA activity, was isolated from normal spleen extracts. We conclude that the adenosine deaminating activity observed in patients with ADA-CID is not ADA. The activity may be due to an enzyme whose principal substrate may be another metabolite. The presence of this non-ADA deaminating activity in normal spleen suggests that the observed activity in ADA-CID tissue is not due to a mutant form of ADA and that the inhibited enzyme activity reported by Trotta et al. may be due to an amplification of this non-ADA deaminating enzyme.
Es wird über eine äußerst seltene chronische Hyperurikämie bei einem 2œjährigen Kleinkind als Ausdruck einer familiärgichtischen Diathese berichtet; gleichzeitig bestehen zentralnervöse Symptome (statische und lokomotorische Ataxie, Dysarthrie) sowie Zeichen einer Niereninsuffizienz (Ausdruck vielleicht einer angeborenen Fehlbildung oder Nephronophthise). Es wird eine Koordination aller drei Symptomkomplexe vermutet und gezeigt, daß sich eine an das männliche Geschlecht gebundene familiäre Häufung derselben (in der mütterlichen Familie) nachweisen läßt.
Summary
The case is reported of chronic hyperuricaemia in a 2œ-year old boy; there also were central nervous system symptoms (static and locomotor ataxia, and dysarthria) and evidence of renal impairment. It is thought that the hyperuricaemia and the cerebral and renal involvement were related. On the maternal side there was a high incidence of sex-linked (to the male) gouty diathesis. Only one other case of childhood hyperuricaemia with familial gouty diathesis has apparently been reported in the medical literature.
Resumen
Diátesis familiar gotosa y síntomas cerebrales y renales en un niño pequeño
Se informa sobre una hiperuricemia crónica, extraordinariamente rara, en un niño de 2 años y medio como expresión de una diátesis gotosa familiar. Simultáneamente existían síntomas nerviosos centrales (ataxia locomotriz y estática, disartría) así como signos de insuficiencia renal (expresión quizás de una malformación congénita o de una tisis nefronal). Se supone la coordinación de los tres complejos sintomáticos y se demuestra una mayor frecuencia familiar de los mismos ligada al masculino, en la familia de la madre.
Adenine compounds can be measured in picomole amounts using liquid chromatography of the fluorescent 1, N-etheno derivatives. The limit of detection for the etheno derivatives in tissue extracts, however, is tissue-dependent due to interference by nucleotides and fluorescent components which are normally present. Prior to derivatization nucleotides were partially removed from extracts of lymphocytes and erythrocytes by treatment with Dowex AG1-X2 anion exchange resin. Samples were analyzed using either a Partisil PXS 10/25 SCX column eluted with 100 mM NH4H2PO4, pH 4.5, at a flow rate of 2 ml/min; or using two μBondapak/C18 reversed-phase columns eluted with 5 mM KH2PO,4:25% methanol (V/V) pH 7.5, at a flow rate of 1 ml/min. Adenosine was found to be 0.07 nmole/ml in normal adult human plasma. The urine of a child with severe combined immunodeficiency disease associated with absence of adenosine deaminase contained a normal amount of adenosine (5–6 nmole/ml), but contained a high level (∼60 nmole/ml) of deoxyadenosine. Deoxyadenosine was not detected (
Skin fibroblast cultures were utilized to study the mode of inheritance of a mutant feedback-resistant phosphoribosylpyrophosphate synthetase in a gouty family with purine overproduction. Selective conditions were applied to allow the survival in culture of mutant cells only. Whereas in the male gouty propositus the cell culture was homogeneous for the mutant enzyme, in the cell culture from his nongouty mother two cell populations were demonstrated, one normal and the other mutant. The mosaicism in the mother is compatible with X-linkage of the enzyme. From this finding, together with the clinical and biochemical data available, it is concluded that in this family the enzyme mutation is transmitted in a X-linked recessive pattern.Copyright © 1977 S. Karger AG, Basel
Recent observations of urate excretion by the kidney in genetic overproducers of urate have contributed to our understanding of the mechanisms of renal damage in gout. Some of these overproducers showed normal serum urate concentrations when their urine urate excretions were high, putting them at risk from uric acid crystalluria and calculi. Others developed acute renal failure which was completely reversed by an intense alkaline diuresis. Some overproducers developed varying degrees of renal insufficiency while others members of the same family with the same genetic mutation retained normal renal function. How can these observations be reconciled with existing knowledge of the gouty kidney?
Fibroblast strains from 12 patients with xeroderma pigmentosum had lower than normal rates of DNA repair, as determined by
autoradiographic studies of ultraviolet-induced unscheduled nuclear DNA synthesis. The nuclei in binuclear cells, obtained
by fusing fibroblasts from certain pairs of these strains, had a greater rate of DNA repair than the nuclei of either strain's
unfused mononuclear cells. These results indicate that complementary corrections of the strains' repair defects had occurred
in the fused cells. Four complementation groups were found, indicating that at least four mutations caused decreased DNA repair
among these 12 strains. The unfused mononuclear cells of each group had a characteristic rate of repair that differed from
the rates of the other groups.
Nine patients who ultimately proved to have acute gouty arthritis did not have urate crystals demonstrable by compensated polarized light in the first joint fluid aspirated despite leukocyte counts as high as 100,000/mm3. In 6 cases crystals were found in fluid from the same joint 5 hours to 1 day later. Factors that might explain the difficulty in identifying crystals include aspiration of the wrong site because diffuse swelling obscured predominant involvement of a bursa or adjacent small joint, loculation within a joint, crystal dissolution leaving only tiny birefringent chunks, and inexpert or insufficient search. Some cases remain without any tentative explanation. The possibility of acute gouty arthritis should not be excluded if crystals are not demonstrable in the first search of joint fluid. Repeated searches for typical monosodium urate crystals may be required for diagnosis.
The development of automated techniques in the clinical laboratory, which routinely includes the measurement of uric acid, has raised important questions concerning the clinical significance of abnormal serum urate values. Although numerous studies have focused on the relevance of hyperuricemia, the significance of hypouricemia has been elucidated only recently. As late as 1969 Lawee noted that a serum urate value below 2.6 mg/100 ml was ignored by the attending physician in all but 1 of 44 patients. In the present article the author wishes to focus on the nature, frequency, and significance of hypouricemia. The following aspects are dealt with: decreased uric acid production; increased uric acid excretion, and mechanism unknown. (51 references).
The American Rheumatism Association subcommittee on classification criteria for gout analyzed data from more than 700 patients with gout, pseudogout, rheumatoid arthritis, or septic arthritis. Criteria for classifying a patient as having gout were a) the presence of characteristic urate crystals in the joint fluid, and/or b) a tophus proved to contain urate crystals by chemical or polarized light microscopic means, and/or c) the presence of six of the twelve clinical, laboratory, and X-ray phenomena listed in Table 5.