Effect of Penicillamine on Cystinuria

Crawhall, J. C.; Scowen, E. F.; Watts, R. W. E.

doi:10.1136/bmj.1.5330.588

Cited by 243 publications

(70 citation statements)

References 3 publications

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“…The cystine was accounted for by the excretion of the disulfide of L-cysteine and D-penicillamine. The present report suggests that the disulfide of cysteine and penicillamine (22,23) The results of the present study are most compatible with asymmetrical disulfide's being a "normal" metabolite that exists in trace amounts in human blood plasma and urine. It is probably metabolized by the normal subject, largely to sulfate.…”

Section: Discussionsupporting

confidence: 74%

“…The small extraction of cystine, like that of most amino acids, demonstrates a high degree of reab-sorption by the renal tubules and agrees with the observation of Rosenberg, Downing, and Segal that cystine does nlot compete with lysine, arginine, and ornithine for uptake by rat kidney slices, although the three basic amino acids do compete (21). Crawhill, Scowen, and Watts have reported a remarkable and prompt reduction in urinary cystine in cystinuria by the administration of D-penicillamine (22,23). The cystine was accounted for by the excretion of the disulfide of L-cysteine and D-penicillamine.…”

Section: Discussionsupporting

confidence: 68%

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Cystinuria: Metabolism of the Disulfide of Cysteine and Homocysteine*

Frimpter¹

1963

J. Clin. Invest.

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The isolation and identification of the asymmetrical disulfide of L-cysteine and L-homocysteine, hereafter referred to as "mixed disulfide," were previously described (1). At that time the amino acid had been found only in the urine of patients with cystinuria.This paper attempts to explain the origin and significance of the mixed disulfide. In approaching this work, I first assessed the natural occurrence of mixed disulfide. To increase the compound's sensitivity to detection in a complicated area of the chromatogram, it was rendered radioactive by the administration of L-methionine-S35. The radioactive mixed disulfide was isolated from the urine of a patient with cystinuria after he was fed L-methionine-S35, and the specific activities of the two sulfur atoms were compared to each other and to cystine sulfur. The mixed disulfide, synthesized with S35 was administered to a patient with cystinuria, and its fate was studied. Finally, to define the role of the kidney in metabolism of the compound, concentrations in renal venous blood were compared with those in arterial blood. METHODSFree amino acids of urine and plasma were measured by the method of Spackman, Stein, and Moore (2). '5-labeled, mixed disulfide is 100 + 3% recoverable when added to urine or to plasma prior to picric acid precipitation of proteins (3). The compound is, however, unstable under the conditions suggested by Stein and Moore for oxidation of cysteine to cystine for chromatography (4). Accordingly, specimens were analyzed without this step, except when examination for the possible occurrence of homocysteine was desirable. Radioactive mixed disulfide, when added to plasma, dialyzed from cellophane in a manner consistent with its being free and unbound to plasma proteins (5). Fractions of the column effluent were collected by a stream-splitting technique (6).* This study was supported by grants H-4148 and FR-47 from the National Institutes of Health, U. S. Public Health Service.t Senior Research Fellow, New York Heart Association.Radioactivity in fractions of column effluent was determined by liquid scintillation counting. Two-ml fractions were poured directly into counting vials, and the fraction collection tubes were rinsed into the counting vials with 10 ml of a dioxane phosphor system.1 This method yielded an over-all counting efficiency of 30%o.For identification of mixed disulfide in urine, fractions were collected by the stream-splitting technique. The pooled fractions containing the material were desalted on Dowex 50 X 4 (H+) (7) and evaporated to dryness. The specimens were then subj ected to oxidation with performic acid (8), and the resultant cysteic and homocysteic acids were determined by 2-dimensional paper chromatography, with butanol: acetic acid: water (120: 30: 50) versus butanol: pyridine: water (1: 1: 1) (9).The Ninhydrin colored spots were eluted with an ethanolic copper sulfate solution and compared with standards in a spectrophotometer (10).Fifty Ac of L-methionine-S' with a SA of 17 ,uc per mg was administered orally ...

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 68%

Cystinuria: Metabolism of the Disulfide of Cysteine and Homocysteine*

Frimpter¹

1963

J. Clin. Invest.

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“…Granted that movement and rotation are possible between the atoms, this difference in configuration could explain the failure of cystathionine to be involved in the mechanism of Dent and Rose (7). The high clearance ratios of the asymmetrical disulfide of cysteine and homocysteine in cystinuria and of the disulfide of D-penicillamine and L-cystine, the latter observed after therapy of cystinuria with D-penicillamine (11), are compatible with this concept.…”

Section: Methodssupporting

confidence: 73%

Renal Clearance of Cystathionine in Homozygous and Heterozygous Cystathioninuria, Cystinuria, and the Normal State*

Frimpter¹,

Greenberg²

1967

J. Clin. Invest.

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“…During our investigations of the action of D(-) -penicillamine 1 in the treatment of cystinuria (1,2) we have measured plasma and urinary amino acids before and during therapy with this drug. Dent, Senior, and Walshe (3) reported that the renal clearance of cystine was close to the glomerular filtration rate (GFR) in the disease; this was confirmed in three out of four patients studied by Arrow and Westall (4) and in three of the four patients studied by Frimpter and associates (5).…”

Section: Introductionmentioning

confidence: 99%

The Renal Clearance of Amino Acids in Cystinuria*

Crawhall¹,

Scowen²,

Thompson³

et al. 1967

J. Clin. Invest.

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Summary. The renal clearance of cystine, lysine, ornithine, arginine, and glycine has been compared with the simultaneously determined glomerular filtration rate in nine cystinuric patients. Five were studied before and after stabilization on penicillamine therapy, two were studied only while taking penicillamine, and two were studied only in the absence of penicillamine administration. The renal clearances of cysteine-penicillamine and of penicillamine disulfide were also determined in the patients who were taking the drug.Amino acids were determined by quantitative ion exchange chromatography, and the reliability of the method has been evaluated in terms of its reproducibility and of the recovery of known amounts of amino acids added to plasma and to urine. The plasma levels of cystine and of the basic amino acids were less than normal in all the patients. Cysteine-penicillamine and penicillamine disulfide were cleared by the kidney at rates similar to that of cystine. Two of the patients had glycine clearances that were considerably above the normal value. The renal clearance of cystine exceeded the glomerular filtration rate in six of the nine patients. The results form a continuum from values approximately equal to the glomerular filtration rate to values about twice this amount. The renal clearances of cystine and of the basic amino acids vary independently of one another in the disease.The significance of these results is discussed in terms of the nature of the renal tubular transport defect that underlies the disorder.

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Effect of Penicillamine on Cystinuria

Cited by 243 publications

References 3 publications

Cystinuria: Metabolism of the Disulfide of Cysteine and Homocysteine*

Cystinuria: Metabolism of the Disulfide of Cysteine and Homocysteine*

Renal Clearance of Cystathionine in Homozygous and Heterozygous Cystathioninuria, Cystinuria, and the Normal State*

The Renal Clearance of Amino Acids in Cystinuria*

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