Leukocyte and Liver Glutaminase in Lysinuric Protein Intolerance

Simell, Olli; Perheentupa, Jaakko; Visakorpi, J. K.

doi:10.1203/00006450-197210000-00008

Cited by 8 publications

(3 citation statements)

References 18 publications

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“…The nature of the association between the slow synthesis of urea and the renal leakage of diamino acids in LPI has not been clarified (5,6,12,13). We suggest that the availability of ornithine, the carrier molecule upon which urea is formed in the liver, is decreased because of a transport defect severe enough to impair the function of the cycle.…”

Section: Abstract Lysinuric Protein Intolerance (Lpi) Ismentioning

confidence: 99%

Renal Handling of Diamino Acids in Lysinuric Protein Intolerance

Simell¹,

Perheentupa²

1974

J. Clin. Invest.

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A B S T R A C T Lysinuric protein intolerance (LPI) isa rare recessively inherited disease in which one of the fundamental physiological defects is in the mechanism by which diamino acids are transported by the kidney.The purpose of the present studies was to examine that mechanism in four controls and seven patients with LPI. Two types of studies were conducted. In the first set, the renal handling of l-arginine and l-ornithine was evaluated by gradually increasing the plasma concentration of each of these amino acids by constant infusion techniques. In the second set of studies, the possible existence of competitive inhibition between l-arginine, l-ornithine, and 1-lysine was examined.In the control subjects, there was almost complete reabsorption of arginine and ornithine, with increases in their filtered loads to 50-100 times normal. With further increases in the filtered loads of these amino acids, there was a gradual decrease in their fractional reabsorption. Mutual competitive inhibition was suggested by the observation that an increase in the filtered load of one diamino acid was associated with a decrease in the reabsorption of the other two. In LPI, the fasting plasma diamino acid concentrations were significantly lower than in the controls. With low filtered loads, the fractional reabsorption of the diamino acids was clearly below normal. This defect diminished with higher loads. A stepwise increase in the plasma concentration of one diamino acid resulted in a biphasic response. Initially, net tubular secretion of the other diamino acids was noted, but later was followed by return to net absorption. When two diamino acids were infused simultaneously, net absorption of both took place, though less efficiently than in the controls. We conclude that the renal reabsorption mechanism is defective in patients with LPI. With low normal filtered loads, there is increased fractional excretion

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Section: Abstract Lysinuric Protein Intolerance (Lpi) Ismentioning

confidence: 99%

Renal Handling of Diamino Acids in Lysinuric Protein Intolerance

Simell¹,

Perheentupa²

1974

J. Clin. Invest.

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“…Normal activities on substrate excess have been demonstrated for glutaminase (25). carbamyl phosphate synthetase, and the urea cycle enzymes, ornithine transcarbamylase, argininosuccinate lyase, the arginine synthetase system and arginase in liver tissue of the patients (10).…”

Section: Speculationmentioning

confidence: 99%

“…The decreased plasma concentrations of arginine and ornithine are not alone a sufficient explanation for such ornithine deficiency, because their ranges overlap with normal, and some cystinuric subjects have similarly decreased plasma diamino acid concentrations (5) but no hyperammonemia. Because the metabolic clearance rates of arginine and ornithine from plasma are delayed in LPI (26), a defect in the transport of these diamino acids into or within the liver cells has been suspected (25,26).…”

Section: Speculationmentioning

confidence: 99%

Diamino Acid Transport into Granulocytes and Liver Slices of Patients with Lysinuric Protein Intolerance

Simell

1975

Pediatr Res

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A m i n o acid t r a n s p o r t liver d i a m i n o acids urea cycle ExtractThe amounts of 14C-labeled lysine, arginine, and ornithine taken up by isolated granulocytes of 11 patients with lysinuric protein intolerance ( L P I ) and of 16 control subjects were measured. Transport against a concentration gradient was evident in all. The initial 5-min uptake was measured in a series of substrate concentrations varying from 0.025-4.0 mM. One transport system was seemingly present for all three amino acids. The rates of transport into the granulocytes in the patients and control subjects were comparable. The V,,,, in millimoles x kilogram of cell w a t e r ' x 5 min-l, ranged only from 0.30-0.38 in the patients and from 0.32-0.34 in the control subjects. The K, values were 0.06 apd 0.06 m M for lysine, 0.05 and 0.06 for arginine, and 0.10 and 0.09 m M for ornithine in the patients and control subjects, respectively.The transport of the nonmetabolizable diamino acid analog, homoarginine, into liver slices of three patients and five control subjects was also studied. There was no clear difference in the time course of uptake a t 0.05 m M homoarginine concentration in the medium. In kinetic studies of two patients and three control subjects, a t least two transport systems were evident. The "large capacity, low affinity" system had V,,, of 0.43 and 3.08 mmol x kg cell water-x 15 min-I and K, of 0.18 and 2.49 m M in the patients and control subjects, respectively. The "small capacity, high affinity" system had V,,, of 0.07 and 0.14 mmol x kg cell waterx 15 m i n 1 and K, of 0.03 and 0.05 mM, respectively. The V,,, of the large capacity, low affinity system in the patients was only 1/7 of that in the control subjects, showing clearly impaired diamino acid uptake by the liver cells in LPI.

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Hyperdibasicaminoaciduria and Hyperammonemia in Familial Protein Intolerance

Kato¹

1976

Arch Pediatr Adolesc Med

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\s=b\A 3-year-old boy with hyperdibasic\x=req-\ aminoaciduria and hyperammonemia showed characteristics of familial protein intolerance (FPI). Oral loading tests of lysine and arginine disclosed a remarkably reduced capability for intestinal absorption of these amino acids. Because urinary excretion and renal clearance of dibasic amino acids were only moderately elevated in the patient, the conspicuously decreased serum concentration of lysine, arginine, and ornithine was attributed to the defect in intestinal absorption. A possible explanation for elevated blood ammonia levels in FPI is that it is due to a deficiency of arginine and ornithine in the urea cycle that in turn results from a severe impairment in absorption of the amino acids by the gut mucosa.

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Leukocyte and Liver Glutaminase in Lysinuric Protein Intolerance

Cited by 8 publications

References 18 publications

Renal Handling of Diamino Acids in Lysinuric Protein Intolerance

Renal Handling of Diamino Acids in Lysinuric Protein Intolerance

Diamino Acid Transport into Granulocytes and Liver Slices of Patients with Lysinuric Protein Intolerance

Hyperdibasicaminoaciduria and Hyperammonemia in Familial Protein Intolerance

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