Showing papers on "Urea cycle published in 1979"

Activities of urea-cycle enzymes in chronic liver disease.

Abstract: The activities of urea-cycle enzymes were measured in liver biopsies of patients suffering from chronic-persistent hepatitis (CPH), chronic-active hepatitis (CAH) and liver cirrhosis. Most of the activities of urea-cycle enzymes did not differ in the case of CPH as compared to controls. Chronic-active hepatitis and liver cirrhosis are associated with a significant (p less than 0.05) decrease of enzyme activity as compared to normal persons. Most of the urea-cycle enzymes are significantly decreased in patients with CAH in comparison with CPH. No significant differences can be demonstrated in the case of CAH as compared to patients with complete cirrhosis. In conclusion, progression of chronic liver disease is associated with increasing alterations of enzyme activities catalyzing a liver specific metabolic pathway. The decrease of the activities of the key enzymes of the urea cycle (Carbamylphosphate-Synthetase and Arginino-succinate-Synthetase) is nearly identical both in CAH and liver cirhosis, although CAH may be a reversible disease. Therefore, marked alterations in the metabolic pathway of ammonia detoxification seem to preceed the histological manifestation of irreversible liver damage.

Regulation of Urea Synthesis in Rat Liver Inhibition of Urea Synthesis by L-Norvaline

Abstract: The mechanism of inhibition of urea synthesis by L-norvaline was investigated in vitro with perfused rat liver and purified enzymes of the urea cycle, and in vivo. L-Norvaline caused potent inhibition of urea synthesis from ammonium chloride in the perfused liver and increases in citrulline and arginine in the liver. The increased ratio of the concentration of arginine to ornithine suggested that the main inhibition step of the urea cycle with L-norvaline is arginase. Kinetic studies with purified enzymes showed that L-norvaline inhibits arginase as well as ornithine transcarbamylase and argininosuccinate synthetase competitively with respect to their amino acid substrates, arginine, ornithine, and citrulline, respectively. The inhibition of arginase by L-norvaline was much stronger at pH 7.5 than at pH 9.7. An in vivo experiment was performed to determine whether the same inhibition mechanism operates in the rat. Judging from a decrease in urea and an increase in ammonia in the liver, intraperitoneal injection of L-norvaline caused inhibition of urea synthesis in vivo. The same conclusion, that L-norvaline inhibits urea synthesis mainly through the inhibition of arginase, was also obtained in the in vivo experiment showing an increased ratio of the concentration of arginine to ornithine. The concentration of acetylglutamate was increased by the addition of L-norvaline both in the perfused liver and in the liver in vivo, probably as a result of secondary effects of the increase in arginine.

Studies of renal urea cycle enzymes. I. Renal concentrating ability and urea cycle enzymes in the rat during protein deprivation.

Abstract: Activities of renal urea enzymes were studied in normally fed (21% dietary protein) rats and rats deprived of protein (6% dietary protein) for 3 weeks. Protein deprivation resulted in growth retardation and defective urine concentrating ability. Compared to rats on an optimal diet containing 21% of protein, the protein starved animals had decreased concentrations of protein and urea in serum, reduced urinary excretion of urea and decreased levels of all five urea cycle enzyme activities in the liver. In the kidney, however, protein malnutrition resulted in a significant increase in arginase specific activity from 11.5 ± 1.1 to 16.3 ± 1.5 (M ± SD) whereas the other urea cycle enzymes remained unchanged. It is postulated that this increase in renal arginase might be an early compensatory mechanism to preserve a net synthesis of urea in a situation involving arginine deficiency, thereby preserving an intact hypertonic gradient in the renal medulla.

The effect of thioacetamide on urea cycle enzymes of rat liver.

Abstract: The urea cycle enzymes, carbamoyl-P-synthetase, ornithine transcarbamylase, arginase and other enzymes related to ammonia metabolism, such as glutamate dehydrogenase, glutamine synthetase and alanine and aspartate aminotransferases,have been studied in thioacetamide-induced liver disease in rats. Urea and ammonia were determined both in serum and in liver extracts. Glutamate and aspartate were determined in liver extracts. There was a marked decrease (in brackets: fraction of control) in carbamoyl-P-synthetase (0.23), ornithine transcarbamylase (0.36) and arginase (0.62). The accumulation of ammonia (3.22) and the decreased urea level (0.80) are well known indications of liver failure. Glutamate dehydrogenase and glutamine synthetase increased respectively to 1.50 and 1.33, and the changes in glutamate and aspartate levels were respectively 1.68 and 0.92; this indicates that the metabolic route: 2-oxoglutarate leads to glutamate leads to glutamine is increased, and thereby compensates for the low rate of urea formation. Aminotransferase activities were respectively 0.43 and 0.25. No significant differences were found in serum aminotransferases, or in the concentrations of ammonia and urea.

Orotic aciduria and increased nitrogen catabolism in rats.

Abstract: In vitro incorporation of [14C] bicarbonate into orotic acid by rat liver slices was used to study the rate of orotic acid (OA) biosynthesis in the presence of physiological (0.73 mM) and saturation concentrations (5 mM) of NH4Cl. The influence of body size on OA synthesis in rats fed purified L-amino acid diets with (C) or without (-Arg) was examined. OA biosynthesis was significantly greater at both NH4Cl concentrations examined in liver slices obtained from -Arg rats for all sizes of rats. A linear decrease (r = 0.92) in OA synthesis as a function of body size was observed for rats fed either of the diets. The rate of OA biosynthesis was also found to increase linearly (r = 0.98) in livers from rats fed increasing dietary protein when determined by incubation with physiological concentrations of NH4Cl. OA biosynthesis was also found to increase with increase in length of fasting. Alteration in urinary OA and urea confirm these rates of synthesis. These results support the hypothesis that when the urea cycle is overtaxed, carbamyl phosphate (CP) synthesized intramitochondrially by CP synthetase I may be shunted into pyrimidine biosynthesis.

Hormonal regulation of three urea cycle enzymes in rat fetal liver.

Abstract: The purpose of such studies is to identify the hormones that act on the developmental formation of individual urea cycle enzymes, namely argininosuccinate synthetase, argininosuccinate lyase and arginase in the rat fetal liver. The development of argininosuccinate synthetase activity which is completely blocked by the suppression of glucocorticoids in the fetal liver is affected by neither glucagon nor thyroxine. The activity of argininosuccinate lyase which is never changed by the suppression or addition of glucocorticoids, is under the influences of glucagon and thyroxine at a late fetal period and the enzyme activity can be precociously induced in utero by injection of dibutyryl cyclic AMP to fetuses. Cortisol has been shown to precociously stimulate fetal liver arginase activity after an intraperitoneal injection, but the rise in activity at the late fetal period is not completely prevented by suppression of glucocorticoid and it seems that glucagon and thyroxine may also promote its developmental formation just before birth.

Excretion, accumulation and site of synthesis of urea in the snail Pila globosa during active and dormant periods.

Abstract: The pattern of urea excretion in active and dormant phases of the amphibious Indian apple snail, Pila globosa, as well as the possible site and mechanism of urea synthesis in this animal have been studied. 1. Urea may be synthesized in the hepatopancreas of this snail and excreted through the nephridia with the nephridial fluid during the active period of the animals life. In dormant snails, this metabolic excretory waste accumulates in its various organs and body fluids. 2. The possibility of the presence of an ornithine cycle for the synthesis of urea in the hepatopancreas is indicated in this snail.

Lack of mitochondrial enzymes of the urea cycle in human white blood cells.

Abstract: Letter to the Editor: Lack of Mitochondrial Enzymes of the Urea Cycle in Human White Blood Cells

Ammonia metabolism in the rat liver in biliary obstruction.

Abstract: Arginine synthetase activity and ammonia removal in liver slices were determined in rats with obstructive jaundice or acute carbon tetrachloride (CCl4)-induced liver dysfunction and the following results were obtained: (1) Urea synthesis and ammonia removal in liver slices progressively decreased with prolonged biliary obstruction. The effects of ATP and/or ornithine addition were also markedly decreased, particularly in the group with 6 weeks of biliary obstruction. (2) Arginine synthetase activity also fell with prolongation of biliary obstruction and the fall was most pronounced in the 6-week group. (3) The CCl4-induced liver dysfunction group showed a significantly higher level of arginine synthetase activity than the group with 6 weeks of biliary obstruction, but ammonia removal was markedly decreased and the effects of ATP and ornithine addition were prominent. From the results, it is concluded that, due to a fall in the enzyme activity of the urea cycle in obstructive jaundice, liver dysfunction can easily occur with prolongation of the obstruction, while hepatic urea cycle dysfunction is brought about by severe metabolic disruption in the liver damaged by CCl4.

Lysinuric protein intolerance ( LPI ): treatment with citrulline and lysine

Abstract: LPI is an autosomal recessive defect of diamino acid transport in renal tubular and intestinal epithelium, and hepatocytes. This leads to deficiency of ornithine and other urea cycle intermediates, and inadequate function of the cycle which results in hyperammonemia after protein intake, and protein aversion. Lysine shortage may contribute to the growth failure of the patients. Our patients have earlier been treated with an arginine supplement. We have now shown that, while the intestinal absorption is very poor for arginine, it is intact for citrulline, another urea cycle intermediate. Since autumn 1976 our patients have been given 1.5 g/kg of dietary protein daily supplemented with 2-3 g citrulline and 1-2 g lysine. The protein aversion decreased in 13/21 patients, growth accelerated in 12/21, and urinary orotic acid excretion rate normalized in 9/11 as a sign of improved nitrogen tolerance. 4 patients had very fragile and sparse hair; this normalized during the therapy. Gastrointestinal complaints appeared during the treatment in 6/21; these disappeared when lysine supplementation was stopped. Hepato- and splenomegalia, increased plasma lactate dehydrogenase, leukocytopenia and trombocytopenia, and fasting plasma and urinary amino acids remained unchanged. They may depend on lysine deficiency. The severe intestinal transport defect of lysine seems to invalidate the oral route for lysine supplementation. We suggest that citrulline, possibly with lysine, should replace arginine in the treatment of LPI.

Urea production inRana pipiens effects of aldosterone on urea cycle enzymes

Abstract: 1. The rates of {14C}-HCO3− incorporation into liver urea cycle intermediates were measured in vitro in saline dehydrated (0.15 M NaCl) and aldosterone administered frogs,Rana pipiens, in the fall-winter and spring-summer. 2. No increase in the capacity for {14C}-HCO3− incorporation was observed in vitro between seasons or treatment groups, although increases in both unlabeled urea or {14C}-urea production were observed under in vivo or in vitro conditions following saline dehydration or aldosterone administration in spring-summer, but not fall-winter frogs. 3. Analysis of the pattern of incorporation by liver of {14C} into intermediates of the urea cycle revealed a significant build up of arginino-succinate in tap water treated spring-summer frogs, which was restored to levels characteristic of fall-winter frogs following saline dehydration or aldosterone administration. 4. Increases in urea production observed in spring-summer frogs following saline dehydration is mediated by aldosterone, which we propose acts by removing inhibition at the arginino-succinate lyase step of the urea cycle. 5. We propose that the traditional roles assigned in amphibia to aldosterone and corticosterone in mineral and carbohydrate metabolism be re-evaluated in this species.

Modification of biological action of saccharin

Abstract: Members of the urea cycle, i.e. urea, ornithine, arginine and citrulline have been found to reduce the toxicity of saccharin.

[Toxicity of ammonium acetate in rats with acute and subacute galactosamine-induced hepatitis (author's transl)].

Abstract: Ammonia toxicity and the protective effect of arginine thereon were investigated in rats after single and repeated doses of galactosamine. Urea cycle enzymes and ornithine-oxo-acid transaminase activities were measured in rat liver homogenates. Ammonium acetate proved to be less toxic in rats treated with single or repeated doses of galactosamine than in untreated animals. Urea cycle enzyme activities of galactosamine-treated rats were clearly lowered. The protective effect of arginine against lethal ammonia intoxication was found in animals that had been treated with galactosamine as well as in untreated rats. Since the toxicity of ammonium acetate is lower in rats with galactosamine hepatitis, in which the activities of the liver urea cycle enzymes are reduced, it seems likely that ammonia detoxication in galactosamine-poisoned rat liver partly bypasses the urea cycle.