M. Kekomäki

Liver Adenine Nuldeotides: Fructose-Induced Depletion and Its Effect on Protein Synthesis

Intravenous administration of D-fructose to rats rapidly depletes liver adenosine triphosphate and inorganic phosphate; marked elevations of uric acid and allantoin in plasma follow. Concomitantly the incorporation of DL-leucine-1-14C into liver protein is almost completely inhibited.

Depletion of liver adenine nucleotides induced by d-fructose: Dose-dependence and specificity of the fructose effect

Abstract The effect of d -fructose on adenine nucleotide metabolism was studied in rats in vivo by analyzing liver metabolite levels after intravenous fructose injections, and in vitro by measuring allantoin production by the isolated perfused liver after the addition of fructose to the perfusion medium. Significant depression of liver ATP and inorganic phosphate levels was demonstrated after fructose administration. Minimum effective dose was 0.25 m-mole, and maximum depression was observed after 5 min. Analogous, but quantitatively less impressive alterations were produced by l -sorbose and d -sorbitol, whereas d -glucose, d -galactose, d -mannose, d -ribose and 2-deoxy- d -glucose were without effect. In the perfusion studies, marked increase in allantoin production was observed after the addition of d -fructose to the perfusion medium. The minimum effective dose was 0.25 m-mole, corresponding to a mean initial concentration of 4.5 mM in the medium. Allopurinol prevented both the basal allantoin production and the fructose-induced increase. d -galactose, d -ribose, d -sorbitol, sodium- dl -lactate or ethanol did not influence the basal rate of allantoin release. The loss of liver adenine nucleotides in the in vivo experiments was of a similar order of magnitude as the amount of allantoin produced in the perfusion experiments, when calculated per total liver after equal doses of fructose. Therefore, accelerated degradation of preformed purines, rather than increased de novo synthesis, appears to be the main mechanism of fructose-induced increase in uric acid and allantoin production.

Familial protein intolerance with deficient transport of basic amino acids. An analysis of 10 patients.

Familial protein intolerance with deficient transport of basic amino acids (PI), a syndrome of aversion to protein-rich nutrients with hyperammonemia and deficient rise in plasma urea levels following protein intake, failure of growth, hepatomegaly, characteristic amino aciduria, and periods of diarrhea and vomiting in infancy, was described by us in three children in 1965 [22]. Since then, we have seen seven other Finnish and Lapp children with this syndrome. Here we define the clinical features of this disorder, and present further investigations on its biochemistry and a preliminary evaluation of its treatment with arginine.

Lysinuric protein intolerance, an autosomal recessive disease. A genetic study of 10 Finnish families.

Lysinuric protein intolerance (LPI) is characterized by failure to thrive, diarrhea and vomiting associated with protein intake, aversion to protein‐rich food, growth retardation, hepatomegaly, hyperammonemia, and deficient urea formation after an amino nitrogen load, and increased urinary excretion of basic amino acids, especially lysine. LPI has been diagnosed in 16 patients of 10 families in Finland and in one Finnish immigrant in Sweden. In this study data were evaluated to test the autosomal recessive transmission of LPI.

Enzymes of Urea Synthesis in Familial Protein Intolerance with Deficient Transport of Basic Amino Acids

Elevated blood ammonia concentration is characteristic of a number of inborn errors of metabolism [1, 4, 13, 211, in some of which a defect in one of the enzymes of urea synthesis has been demonstrated [la, 21, 241. Perheentupa & Visakorpi [18] have described the syndrome of familial protein intolerance (PI) associated with a cystinuria-like deficient renal and intestinal (re-)absorption of basic amino acids. In this disease, impaired elimination of ammonia is reflected by transient hyperammonemia and failure of the plasma urea concentration to rise after oral or intravenous amino nitrogen loads. L-lysine administration further accentuates this response. Since 1-arginine or 1-ornithine, on the other hand, seem to normalize these findings, arginine deficiency has been suggested to be the cause of the impaired ammonia detoxification [ 181. A specific defect in urea synthesis in the liver might be due to absence or kinetic abnormality of any of the enzymes involved, to substrate deficiency, or to shortage of cofactors. I n the present study, the activity of the enzymes involved in urea synthesis was measured in the livers of 2 children suffering from PI, the kinetics RdIHA and J. PERHEENTUPA

Development of the Ornithine-Urea Cycle

One of the fundamental facts about mammals is that they are intolerant to even modest concentrations of ammonium ion in the cellular environment. Simpler organisms living in a water environment have little problem with nitrogen disposal, since ammonia diffuses freely and is thereby diluted to a very low concentration. During evolution, when a movement from marine to terrestrial environment occurred, a more efficient detoxication mechanism for ammonia was needed, and the formation of urea developed.