The formation of hippuric acid. The influence of benzoate administration on tissue glycine levels

Simkin, J. L.; White, Kenneth L.

doi:10.1042/bj0650574

Cited by 17 publications

(7 citation statements)

References 16 publications

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“…Although hippuric acid excretion was increased, the 5OPuria was not corrected completely. This observation is in keeping with the findings of earlier work, which shows that the metabolic compartmentation of glycine and benzoic acid is different (Simkin & White, 1957). Thus glyoxylic acid, which forms glycine by transamination in the liver, may be far more efficient than glycine itself, for the formation of hippuric acid, presumably because glyoxylic acid forms glycine at a site close to where the hippuric acid is synthesized (Weinhouse & Friedmann, 1951).…”

Section: Discussionsupporting

confidence: 80%

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

et al. 1987

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1. The evidence is accumulating to suggest that glycine, the simplest amino acid, is conditionally essential in man. Benzoic acid, by conjugation with glycine to form hippuric acid, is known to deplete the free glycine pool of the body. Glycine is one substrate for the enzyme glutathione synthase (EC 6.3.2.3) and in the inborn error of metabolism in which glutathione synthase function is defective, increased quantities of 5-oxoproline are excreted in the urine.2. An oral dose of 4-10 g sodium benzoate was given to six normal adults to deplete the metabolic pool of glycine, and the urinary excretion of 5-oxoproline was followed for 6 h. In five of the six, a significant increase in the urinary 5-oxoproline was seen within 3 h.3. These-findings show that 5-oxoprolinuria can result from limited glycine availability, and may provide a useful test for assessing glycine sufficiency in a range of physiological and pathological states.In human nutrition, glycine has generally been considered to be a nutritionally dispensable (non-essential) amino acid (Rose, 1957). There is an absolute requirement for dietary glycine in the chick, apparently to satisfy the demands of uric acid synthesis (Almquist et al. 1940). Moreover, when the rat is faced with either the physiological stress of growth (Griffith, 1929), or the pathological stress of injury or trauma (Sitren & Fisher, 1977), there is a narrow margin between the metabolic demand for glycine and the rate at which glycine can be formed or made available in the body. A marginal state of glycine availability is probably more common than has been appreciated in the past (Jackson, 1983). Recently, we presented evidence to show that glycine might behave as a conditionally essential amino acid in the preterm human infant (Jackson et al. 1981 ; Catzeflis et al.1985). Furthermore, Yu et al. (1985) have shown that in normal adults on a low-protein diet, glycine production in the body is insufficient to satisfy the normal metabolic demand. These findings suggest that glycine insufficiency might occur far more frequently, and be far more widespread than had been recognized (Christensen, 1986). It was for this reason that we had been looking for an index of glycine sufficiency in humans, that would be relatively simple to use in a range of clinical situations. The measurement of 5-oxoproline (50P), L-pyroglutamic acid, in urine possibly represents just such an index. In a range of physiological and pathological conditions in which we had predicted an excessive demand for glycine, we were able to demonstrate increased urinary excretion of 50P (Jackson et al. 1986).50P is a normal intermediate of the y-glutamyl cycle (Meister, 1983) and may be detected at low levels in the urine of healthy individuals. Excessive loss of 5 0 P in the urine, 5-oxoprolinuria (SOPuria), may be found in inborn errors of metabolism associated with either an increased production (glutathione synthase (EC 6.3.2.3) deficiency) or decreased utilization (5-oxoprolinase deficiency) of 50P by the body (Meister, 1...

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Section: Discussionsupporting

confidence: 80%

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

et al. 1987

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“…This study confirms the observation that sodium benzoate is converted largely to hippurate (Simkin and White, 1957;Batshaw et al, 1982;Brusilow et al, 1984).…”

Section: Discussionsupporting

confidence: 92%

“…On the other hand, Batshaw and colleagues (1982), published studies on a patient in whom the plasma concentration of glycine decreased below the normal range when the benzoate dosage was accidentally increased from 250 to 800 mg kg -1 per day. Moreover, a reduction in the content of free glycine in the liver was found in rats after injection of 4mmolkg -1 benzoate (Simkin and White, 1957). This dosage was close to those used in the present study.…”

Section: Discussionsupporting

confidence: 71%

“…This is in contrast to the reasonable expectation (Bachmann, 1984) that slightly more than the ingested dose of benzoate should be excreted because of the endogenous production of hippurate, which is approximately 0.14 mmolper day in controls and 0.31 mmol per day in hyperammonaemic infants (Green et al, 1983). It has been postulated that the incomplete conversion of ingested benzoate to hippurate is a result of decreased availability of glycine (Simkin and White, 1957). To test this hypothesis, we compared the excretion of hippurate during therapy with benzoate in patients with urea cycle disorders and with non-ketoic hyperglycinaemia.…”

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confidence: 47%

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Excretion of hippuric acid during sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia

Barshop

Breuer

Holm

et al. 1988

J of Inher Metab Disea

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In patients with non-ketotic hyperglycinaemia and two patients with urea cycle disorders treated with varying doses of sodium benzoate there was linear correlation between intake of benzoate and excretion of hippurate. Patients with non-ketotic hyperglycinaemia excreted significantly more benzoate in the form of hippurate than patients with urea cycle disorders (74 +/- 7.0 vs 41 +/- 3.6%). The plasma concentration of glycine decreased following benzoate treatment only in the patients with non-ketotic hyperglycinaemia. The observed difference between the two groups in the excretion of hippurate seems to support the concept that glycine availability may be limiting in benzoate therapy for some patients.

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“…Our previous excretion study revealed that p-FBA and p-FHA were the major metabolites detected in rat urine (Pan et al, 2009), and it was commonly known that hippuric acid was formed by the conjugation of benzoic acid with glycine in mitochondria (Simkin and White, 1957). Thus, the reason why p-FHA was not detected in the in vitro incubation system or in vivo is probably that RBCs have no mitochondria.…”

Section: Discussionmentioning

confidence: 96%

Metabolism of Bis(4-fluorobenzyl)trisulfide and Its Formation of Hemoglobin Adduct in Rat Erythrocytes

Pān

Sun

et al. 2013

Drug Metab Dispos

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Bis(4-fluorobenzyl)trisulfide (BFBTS) is a promising new antitumor agent under investigation. It was metabolized rapidly in vivo in rat, but the metabolic fate and primary site of metabolism have not been clarified. In this study, we investigated the role of blood in the metabolism of BFBTS and compared the BFBTS metabolic potencies in whole blood, plasma, and red blood cells (RBCs) in vitro. Three major metabolites of BFBTS [bis(4-fluorobenzyl) disulfide, para-fluorobenzyl-mercaptan, and para-fluorobenzoic acid] were detected in RBCs and whole blood. Significant metabolism of BFBTS was observed in RBCs that were identified as the primary site of BFBTS metabolism. Thiols, including endogenous thiols and hemoglobin, were proven to be the critical factor in BFBTS metabolism. S-Fluorobenzylmercaptocysteine Hb (hemoglobin) adducts were characterized in vitro at BFBTS concentration of 250 mM and higher, whereas such Hb adducts were not detected in RBCs from Sprague-Dawley rats receiving a single intravenous injection of BFBTS at a high dose of 50 mg/kg. Liquid chromatography-tandem mass spectrometry results revealed that adduction induced by BFBTS was prone to take place at Cys125 of globin b chains. Otherwise, glutathionylation of Hb was also observed that may be attributed to the oxidative effect of BFBTS. In summary, BFBTS was unstable when it met with thiols, and RBCs were the main site of BFBTS metabolism. Hb adducts induced by BFBTS could be detected in vitro at high concentration but not in vivo even at high dose.

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The formation of hippuric acid. The influence of benzoate administration on tissue glycine levels

Cited by 17 publications

References 16 publications

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

Excretion of hippuric acid during sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia

Metabolism of Bis(4-fluorobenzyl)trisulfide and Its Formation of Hemoglobin Adduct in Rat Erythrocytes

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