Sulfur amino acid metabolism in cystinuria: A biochemical and clinical study of patients

Mårtensson, Jerker; Denneberg, Torsten; Lindell, Å.; Textorius, Ola

doi:10.1038/ki.1990.20

Cited by 23 publications

(9 citation statements)

References 43 publications

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“…That ascorbate protects against experimental GSH deficiency suggests that it may be useful in treating patients with inborn deficiencies of y-glutamylcysteine and GSH synthetases (66), premature newborns, and others deficient in GSH (67)(68)(69). Although ascorbate can induce oxidative stress (see ref.…”

Section: Resultsmentioning

confidence: 99%

Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.

Mårtensson

Meister²,

Mrtensson³

1991

Proc. Natl. Acad. Sci. U.S.A.

255

123

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Glutathione deficiency in newborn rats, produced by admiisttion of L-buthionine-(SR)-sulfoximine, a transition-state inactivator of y-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung. These tissues, especially their mitochondria, undergo severe damage and the animals die within a few days. When glutathione levels are markedly decreased, ascorbate levels decrease leading to formation of dehydroascorbate, which is degraded. Ascorbate has high antioxidant activity, but it (and other antioxidants such as at-tocopherol) must be maintained in reduced forms. These studies show in vivo that an important function of glutathione is to maintain tissue ascorbate. Administration of large doses of ascorbate (but not of dehydroascorbate) to buthionine sulfoximine-treated newborn rats decreases mortality, leads to normal levels of ascorbate, and spares glutathione. Newborn rats given lower doses of buthionine sulfoximine develop cataracts that, as shown previously, can be prevented by giving glutathione monoester; as found here, such cataracts can be partially prevented by administration of high doses of ascorbate or dehydroascorbate. Ascorbate spares glutathione indicating that these compounds have similar antioxidant actions. Ascorbate may have reductive functions that are not efficiently performed by glutathione. Although glutathione normally functions to maintain ascorbate, a-tocopherol, and other cellular components in reduced states, ascorbate can serve as an essential antioxidant in the presence of severe glutathione deficiency.

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Section: Resultsmentioning

confidence: 99%

Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.

Mårtensson

Meister²,

Mrtensson³

1991

Proc. Natl. Acad. Sci. U.S.A.

255

123

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“…The brush border mem brane transport is dependent on sodium and may possibly occur at the same site as cysteine. Our research group has noted previously that the sulfhydryl compounds Z)-penicillamine and tiopronin exert their effects in cystinuria not only by the formation of a mixed disulfide in urine, but probably also by promoting an increased intracellular cystine metabolism [29]. It has also been reported that the sulfhydryl compound mercaptoethanol might improve the intracellular utilization of cystine by facilitating the transport of cystine into the cells [30].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

Lindell¹,

Denneberg²,

Edholm³

et al. 1995

Nephron

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As with many other amino acids the transport of cystine across the tubular epithelium is coupled to a parallel transport of sodium. We have studied the effect of a sodium-restricted diet on the urinary excretion of cystine in 13 patients with cystinuria, 7 of whom were treated with the SH compound tiopronin (2-mercaptopropionylglycine). Five of the patients with tiopronin and 5 without were also given sodium bicarbonate. The patients were instructed to follow a sodium-restricted diet during three periods of 2 weeks each. Four levels of sodium intake were obtained including the preexperimental unrestricted diet. The average 24-hour excretion of free cystine increased by 3.1 μmol (0.75 mg) for each millimole increase in urinary sodium (p < 0.001). There was a greater sodium-related increase in excretion of cystine among patients without tiopronin treatment compared with the group with tiopronin (p < 0.01). Withdrawal of sodium bicarbonate resulted in a decrease in the 24-hour cystine excretion (p < 0.05). In the patients treated with tiopronin the excretion of the mixed disulfide increased with increasing urinary sodium (p < 0.05) suggesting a sodium-dependent active tubular reabsorption of this compound as well. We conclude that in spite of a defective proximal tubular reabsorption of cystine in cystinuria the reabsorption can be increased by restricting the intake of sodium. This effect of sodium may have clinical consequences for some cystinuric patients.

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“…The presence or a sulfhydryl compound, 2-mercaptoethanol, improves the cellular uptake of cysteine in leuko cytes by facilitating the transport across the cellular mem branes [29], In a study of the biochemical effects of some sulfhydryl compounds in cystinuria we found signs of nor malization of cystine metabolism following administra tion of tiopronin and D-penicillamine [30], These results indicate that a change in the general metabolism of cys tine and cysteine induced by tiopronin may contribute to the dose-related decrease in urinary excretion of the total cystine observed in our patients.…”

Section: Total Urinary Excretion O F Cystine As Free Cystine and Mixementioning

confidence: 99%

Urinary Excretion of Free Cystine and the Tiopronin-Cysteine-Mixed Disulfide during Long-Term Tiopronin Treatment of Cystinuria

Lindell

Denneberg

Jeppsson

1995

Nephron

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We report the results of a biochemical evaluation of long-term treatment of cystinuria with the SH compound tiopronin (2-mercaptopropionylglycine). The effects of tiopronin were studied by monitoring the urinary excretion of free cystine and the mixed disulfide between tiopronin and cysteine. Thirty-one patients with homozygous cystinuria were treated with tiopronin for 0.4-12 years (mean 7.8 years). The urinary concentration of free cystine was used to adjust the tiopronin dose. In 28 of the 31 patients a mean urinary cystine concentration of less than 1,200 μmol/1 (288 mg/l) was achieved with the final dose. The final daily doses of tiopronin ranged from 250 mg (1.5 mmol) to 3,000 mg (18.4 mmol; mean 1,540 mg; 9.4 mmol). In a majority of the patients the treatment reduced the 24-hour urinary free cystine excretion effectively, on average by 0.61 μmol (0.15 mg)/mg of tiopronin administered. No changes in the efficacy of tiopronin over time were observed, and the frequency of adverse effects was acceptable. To evaluate the effects of tiopronin on the metabolism of cystine we calculated the total urinary excretion of cystine as the sum of free cystine and the amount of cystine corresponding to the cysteine content of the tiopronin-cysteine disulfide. At low doses of tiopronin there was an increase in urinary excretion of the mixed disulfide as well as of total cystine, whereas higher doses were followed by an unexpected decrease in the urinary excretion of these compounds. We conclude that long-term treatment with tiopronin in cystinuria effectively reduces the urinary excretion of free cystine. Monitoring urinary cystine concentration is necessary to achieve adequate individualized doses of tiopronin. Assessment of the mixed tiopronin-cysteine disulfide and the urinary excretion of total cystine shows that tiopronin may interfere with cystine metabolism in a more complex way than through a simple disulfide exchange reaction with urinary cystine.

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Sulfur amino acid metabolism in cystinuria: A biochemical and clinical study of patients

Cited by 23 publications

References 43 publications

Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.

Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

Urinary Excretion of Free Cystine and the Tiopronin-Cysteine-Mixed Disulfide during Long-Term Tiopronin Treatment of Cystinuria

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