Availability Of Glycine Research Articles

Glycine Availability Limits Maximum Hippurate Synthesis in Growing Rats

The rate-limiting step for hippurate synthesis from sodium benzoate (NaB) was investigated in growing rats. Rats fed a glycine-and serine-free L-amino acid diet were injected daily with saline or varying doses of NaB. Growth was monitored for 4 d, after which time rats were killed and livers were assayed for glycine, serine, benzoyl-CoA, benzoyl-CoA ligase and glycine benzoyl-CoA transferase. In control animals, liver glycine and serine concentrations were 2.18 and 1.63 μmol/g wet wt, respectively; benzoyl-CoA was not detectable. In rats injected with 600 mg NaB/kg body wt per day, liver glycine and serine concentrations decreased to 68 and 78% of control values, respectively, and benzoyl-CoA accumulated (0.52 μmol/g wet wt). As the dose of NaB was increased, liver benzoyl-CoA concentration increased, and growth of the rats was markedly impaired. The activities of benzoyl-CoA ligase and glycine benzoyl-CoA transferase were unchanged after NaB treatment. In a second experiment, rats were treated with growth-impairing doses of NaB. When the diet was supplemented with serine and glycine, growth was normalized. liver glycine and serine concentrations returned to control levels, and benzoyl-CoA accumulation was markedly diminished. These results suggest that glycine availability limits maximum hippurate synthesis in vivo.

Potentiation by piridoxilate of the synthesis of hippurate from benzoate in isolated rat hepatocytes. An approach to the determination of new pathways of nitrogen excretion in inborn errors of urea synthesis

The synthesis of hippurate from benzoate as compared to ureagenesis has been investigated in isolated rat hepatocytes. Half-maximal synthesis of hippurate was observed at 0.3 mmol/l benzoate. In the presence of 1 mmol/l benzoate, hippurate synthesis proceeded linearly with time at a rate of 40 ± 10 μmol · h −1 · g −1 dry weight. This provided less than 10% of nitrogen epuration supported by concomitant urea synthesis (350 ± 82 μmol · h −1 · g −1 dry weight). The incorporation of benzoate to hippurate was markedly limited by the availability of glycine. Half-maximal hippurate synthesis was observed at 2 mmol/l glycine. In the absence of glycine, piridoxilate, a glyoxylate derivative, markedly potentiated hippurate synthesis. Half-maximal stimulation was observed at 10 mmol/l piridoxilate. In the presence of 10 mmol/l piridoxilate, hippurate synthesis (420 ± 35 μmol · h −1 · g −1 dry weight) provided more than 50% of nitrogen epuration supported by urea synthesis. It is concluded that supplementation with nitrogen-free analogues of glycine such as piridoxilate are required to potentiate hippurate synthesis in an attempt to replace ureagenesis as an alternative pathway of waste nitrogen excretion in inborn errors of urea synthesis.

Hippurate synthesis and ammonia metabolism in isolated hepatocytes

The incorporation of benzoate into hippurate by isolated hepatocytes was limited by the availability of glycine. This limitation was unaffected by the addition of ammonia. When isolated hepatocytes were incubated in a solution containing urease, benzoate was completely ineffective in combating ammonia accumulation, while a mixture of α-keto analogues of several amino acids reduced ammonia accumulation by 50%. These findings do not support the use of benzoate to combat hyperammonemia, but they do support the current use of α-keto analogues of amino acids for that purpose.

Antagonistic effects of isovalerate and glycine on plasma choline levels in rabbits

Infusion into rabbits of glycine increased the concentration of plasma choline while infusion of neutralized isovaleric acid which conjugates glycine caused decreased levels. It is suggested that these effects are due to differences in the availability of glycine, convertible to serine which subsequently displaces choline from phospholipids in the base exchange reaction.

Conjugation and urinary excretion of toluene and m-xylene metabolites in a man.

Ingestion of benzoic acid (intermediary metabolite of toluene) by one volunteer subject indicated that the maximum urinary excretion rate of hippuric acid (final metabolite of toluene) was about 190 µmol/min. An almost identical figure for the saturation kinetics of hippuric acid formation has been reported in the literature, and it has been shown to be limited by the availability of glycine for benzoic acid conjugation. The maximum excretory capacity of the kidneys for hippurate is known to be considerably larger than the observed maximum rate of benzoic acid conjugation. In addition the intravenous administration of methylhippuric acid showed that its urinary excretion is rapid, approaching an excretion rate constant of 1.3 h-1. The glycine conjugation of benzoic acid and methylbenzoic acid may well be the ratelimiting step in toluene and, respectively, xylene metabolism. During the inhalation of these solvents, uptake rate may be estimated to equal the full conjugating capacity at a toluene or xylene air concentration of about 780 ppm at rest or of about 270 ppm during moderately heavy work. These data suggest that the body has a relatively large capacity for the conjugation reactions of toluene and xylene metabolism, but the consumption of a large part of easily mobilized glycine may impair the conjugation, and hence excretion, of poorer substrates, e.g., drugs.

Role of glutamine in purine synthesis and in guanine nucleotide formation in normal fibroblasts and in fibroblasts deficient in hypoxanthine phosphoribosyltransferase activity

Normal fibroblasts and fibroblasts deficient in hypoxanthine phosphoribosyltransferase activity were dependent on exogenous glutamine for maximal purine synthesis, particularly after being grown in media without added glutamine. With excess glutamine, the availability of glycine was limiting. The maximal rate of purine synthesis in the mutant cells was about four times that in normal cells. When fibroblasts were incubated with [ 14C]adenine in the absence of glutamine, the incorporation of radioactivity into guanine nucleotides through IMP was severely limited, and the intermediary compounds, xanthylic acid, xanthosine and xanthine accumulated, particularly in the mutant cells. In the presence of glutamine, this accumulation was abolished, a net increase in guanine nucleotide synthesis occurred in mutant cells, but a slight further decrease took place in normal cells. Addition of glutamine to normal fibroblasts produced a marked stimulation of incorporation on [ 14C]hypoxanthine into adenine and guanine nucleotides.

Effect of dietary cholesterol on bile-acid composition of gall bladder bile from guinea pigs.

AbstractThe composition of gall bladder bile acids from control and cholesterol‐fed, anemic guinea pigs was analyzed by thinlayer‐chromatographic and colorimetric techniques. In both control and cholesterol‐fed animals, the gall bladder bile acids constituted about one third of the total bile solids. The main component of the bile acids of both groups of animals was chenodexycholic acid, which was predominantly conjugated with glycine. No cholic acid was present although this is the main bile acid in most mammals. The major difference in bile composition between control and cholesterol‐fed animals was the conjugation pattern of chenodeoxycholic acid. The ratio of glycochenodeoxycholic to taurochenode‐oxycholic acid was high, 6.4, for control animals, and decreased to 2.4 for the cholesterol‐fed, anemic animals. Impaired liver function, limited availability of glycine, and greater efficiency of taurocholanic acids for the disposal of excess cholesterol may be involved in the mechanism for this phenomenon.

Drug Biotransformation Interactions in Man II: A Pharmacokinetic Study of the Simultaneous Conjugation of Benzoic and Salicylic Acids with Glycine

The major route of biotransformation of benzoic acid and salicylic acid in man is conjugation with glycine, resulting in the formation of hippuric acid and salicyluric acid, respectively. Both processes are capacity-limited in the usual dose range and approach a maximum rate following administration of sufficiently high doses of precursor. The rate of hippuric acid formation after oral administration of 5g. benzoic acid in solution is increased markedly by the concomitant administration of glycine. In contrast, the administration of glycine has no effect on the formation of salicyluric acid. Salicylic acid in doses of 1 to 3g. given orally 2 or 3hr. prior to 2.0 to 5.0g. benzoic acid had no measurable effect on the formation of hippuric acid. However, benzoic acid has a pronounced inhibitory effect on the formation of salicyluric acid from salicylic acid. This effect was not prevented by the co-administration of glycine. These results indicate that in man the availability of glycine is rate-limiting in the formation of hippuric acid, but not in the formation of salicyluric acid. Apparently, the inhibitory effect of benzoic acid on the formation of salicyluric acid is not due to competition for glycine but involves another phase in the biotransformation process.