Valproate-induced alterations of coenzyme A and coenzyme A ester concentrations in human kidney tubules metabolizing glutamine.
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Acetyl Coenzyme A↗
Biomedical subjects
G Baverel
Publications and source records attributed to G Baverel.
Glutamine synthesis from aspartate in guinea-pig renal cortex.
1. Glutamine was found to be the main carbon and nitrogen product of the metabolism of aspartate in isolated guinea-pig kidney-cortex tubules. Glutamate, ammonia and alanine were only minor products. 2. Carbon-balance calculations and the release of 14CO2 from [U-14C]aspartate indicate that oxidation of the aspartate carbon skeleton occurred. 3. A pathway involving aspartate aminotransferase, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate dehydrogenase and enzymes of the tricarboxylic acid cycle is proposed for the conversion of aspartate into glutamine. 4. Evidence for this pathway was obtained by: (i) inhibiting aspartate removal by amino-oxyacetate, an inhibitor of transaminases, (ii) the use of methionine sulphoximine, an inhibitor of glutamine synthetase, which induced a large increase in ammonia release from aspartate, (iii) the use of quinolinate, an inhibitor of phosphoenolpyruvate carboxykinase, which inhibited glutamine synthesis from aspartate, (iv) the use of alpha-cyano-4-hydroxycinnamate, an inhibitor of the mitochondrial transport of pyruvate, which caused an accumulation of pyruvate from aspartate, and (v) the use of fluoroacetate, an inhibitor of aconitase, which inhibited glutamine synthesis with concomitant accumulation of citrate from aspartate.
Aminooxyacetic Acid↗
Effect of the antiepileptic drug sodium valproate on glutamine and glutamate metabolism in isolated human kidney tubules.
We studied the effects of sodium valproate, a widely used antiepileptic drug and a hyperammonemic agent, on L-[1-14C]glutamine and L-[1-14C]glutamate metabolism in isolated human kidney-cortex tubules. Valproate markedly stimulated glutamine removal as well as the formation of ammonia, 14CO2, pyruvate, lactate and alanine, but it inhibited glucose synthesis; the increase in ammonia formation was explained by a stimulation by valproate mainly of flux through glutaminase (EC 3.5.1.2) and to a much lesser extent of flux through glutamate dehydrogenase (EC 1.4.1.3). By contrast, valproate did not stimulate glutamate removal or ammonia formation, suggesting that the increase in flux through glutamate dehydrogenase observed with glutamine as substrate was secondary to the increase in flux through glutaminase. Accumulation of pyruvate, alanine and lactate in the presence of valproate was less from glutamate than from glutamine. Inhibition by aminooxyacetate of accumulation of alanine from glutamine caused by valproate did not prevent the acceleration of glutamine utilization and the subsequent stimulation of ammonia formation. It is concluded from these data, which are the first concerning the in vitro metabolism of glutamine and glutamate in human kidney-cortex tubules, that the stimulatory effect of valproate is primarily exerted at the level of glutaminase in human renal cortex.
Adult↗
Effect of lithium on renal transport and utilization of alpha-ketoglutarate in the rat.
Experiments were carried out in the intact functioning rat kidney to study the effect of lithium on both the renal transport of alpha-ketoglutarate (alpha-KG) along the nephron by micropuncture techniques and the renal uptake and peritubular transport of alpha-KG by measuring the renal blood flow, the urinary flow and the rate of renal alpha-KG delivery, filtration, reabsorption or secretion and excretion. At endogenous plasma alpha-KG concentration, 2.3 mM plasma lithium caused an increase in the fractional excretion of alpha-KG, whereas 4.6 mM plasma lithium led to a net secretion of alpha-KG. The micropuncture data indicate that this secretion occurred between the late proximal and the distal tubule, i.e., in the pars recta and/or in the loop of Henle. When plasma alpha-KG concentration was elevated, the two doses of lithium used inhibited the reabsorption of alpha-KG both in the proximal tubule and in the pars recta and/or the loop of Henle. Renal arteriovenous measurements reveal that, at low plasma alpha-KG concentrations, lithium caused a significant decrease in both the renal uptake of alpha-KG and the peritubular transport of this organic anion. These results suggest that the alpha-KG secreted in the pars recta and/or the loop of Henle was synthesized within the renal cells of the latter segments and not transported from the blood to the tubular lumen. At higher plasma alpha-KG concentrations, both the peritubular transport and the renal reabsorption were reduced by lithium.
Absorption↗
Simultaneous synthesis and degradation of glutamine in isolated rat liver cells. Effect of vasopressin.
When hepatocytes suspensions obtained from whole livers of 48-h-fasted rats were incubated in Krebs-Henseleit buffer with a near-physiological concentration (1 mM) of L-[1-14C]glutamine as substrate, the apparent removal of glutamine was low, but the release of 14CO2 was much larger than the enzymatically measured removal of glutamine. This indicates that glutamine was metabolized at rates much higher than those accounted for by the apparent removal of glutamine. This also suggests that glutamine utilization was, at least in part, masked by concomitant synthesis of glutamine from endogenous substrates via glutamine synthetase. Evidence that such synthesis occurred was obtained by: (i) addition of methionine sulfoximine, an inhibitor of glutamine synthetase, which caused a large increase in the apparent removal of glutamine; and (ii) measurement of the specific radioactivity of L-[1-14C]glutamine which was shown to decrease during incubation. Addition of vasopressin (10(-7) M) led to a marked increase in glutamine removal by a dual mechanism: it accelerated flux through glutaminase, the enzyme which initiates the hepatic degradation of glutamine, and inhibited flux through glutamine synthetase.
Animals↗
Stimulation of glutamine metabolism by the antiepileptic drug, sodium valproate, in isolated dog kidney tubules.
The effects of sodium valproate, a widely used antiepileptic drug and an hyperammonemic agent, on glutamine and glutamate metabolism were studied in isolated dog kidney tubules. Valproate markedly stimulated glutamine removal as well as the formation of ammonia, aspartate, pyruvate, lactate, alanine and glucose; the increase in ammonia formation was explained by a stimulation by valproate of flux not only through glutaminase (EC 3.5.1.2) but also through glutamate dehydrogenase (EC 1.4.1.3). By contrast, valproate did not stimulate glutamate removal or ammonia, aspartate and glucose formation from glutamate; this suggests that the increase in flux through glutamate dehydrogenase with glutamine as substrate was secondary to the increase in flux through glutaminase. Accumulation of pyruvate, alanine and lactate in the presence of valproate was much less from glutamate than from glutamine. Inhibition by amino-oxyacetate of accumulation of aspartate and alanine from glutamine caused by valproate did not prevent the acceleration of glutamine utilization and the subsequent stimulation of ammonia formation. These data are consistent with a stimulatory effect of valproate primarily exerted at the level of glutaminase in dog kidney tubules. However, the fact that assayed activity of glutaminase remained unchanged in the presence of valproate suggests that this compound accelerates flux through the latter enzyme by an indirect mechanism probably related to the renal metabolism of this compound.
Alanine↗
Transport and utilization of alpha-ketoglutarate by the rat kidney in vivo.
In order to establish the characteristics of net renal transport and utilization of alpha-ketoglutarate (alpha-KG) in the rat, we have precisely quantified the renal blood flow, the urinary flow and the rates of alpha-KG delivery, filtration, reabsorption or secretion, excretion, uptake or production by an in vivo rat kidney preparation. In normal rats, alpha-KG uptake was higher than alpha-KG reabsorption at both endogenous and elevated plasma alpha-KG concentrations; thus, a net peritubular transport, which was the main supplier of alpha-KG to the renal cells, took place. Saturation of reabsorption and peritubular transport of alpha-KG occurred at blood alpha-KG concentrations about 30 and 150 times above normal, respectively. Acute metabolic acidosis was found to have no effect on renal handling of alpha-KG. At endogenous plasma alpha-KG concentrations, alkalosis converted net renal uptake into net renal production of alpha-KG resulting in addition of alpha-KG by the renal cells both to blood and to the luminal fluid. Elevation of blood alpha-KG concentration restored the renal uptake of alpha-KG. This uptake, which was entirely accounted for by the peritubular transport of alpha-KG, reached a maximum which was lower than that observed in normal and acidotic rats.
Acid-Base Equilibrium↗
Pyruvate carboxylation in glutamine synthesis from alanine by isolated guinea-pig renal cortical tubules.
Isolated guinea-pig kidney cortex tubules were incubated in Krebs-Henseleit buffer containing NaH14CO3 (25 mM) and L-alanine (5 mM). A high rate of alanine metabolism was found to be accompanied by a high rate of both 14CO2 fixation and glutamine synthesis. The fixation of 14CO2 was virtually abolished in the presence of oxalate, a known inhibitor of pyruvate carboxylase, indicating that, in guinea-pig renal cortex, this enzyme is responsible for the synthesis of oxaloacetate in the conversion of alanine into glutamine. More than 90% of the label fixed was found in carbon 1 mainly of glutamine and to a lesser extent of glutamate. In the presence of alanine + NaH14CO3 + MSO, an inhibitor of glutamine synthetase, most of the 14CO2 fixed by pyruvate carboxylase was subsequently released and carbon 1 of glutamate was the only site of labelling. In the presence of alanine + NaH14CO3, the fact that not all the glutamine found was labelled in carbon 1 could be explained by glutamine synthesis from endogenous substrates as well as by glutamine synthesis from alanine after prior equilibration of [4-14C]-oxaloacetate with fumarate; that such equilibration occurred was demonstrated by the observation that [1-14C]-glutamine and [1-14C]-glutamate were synthesized from [1-14C]-alanine.
Alanine↗
Fixation and fate of bicarbonate in glutamine synthesis from alanine in guinea pig renal cortex.
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Alanine↗
Valproate-induced stimulation of renal ammonia production and excretion in the rat.
Administration of valproate, a widely used antiepileptic drug, markedly stimulated the production of ammonia by the rat kidney, resulting in an increase in both the renal venous release and the urinary excretion of ammonia. These effects were associated with a diminution of the plasma concentration of urea which was not accompanied by a stimulation of the urinary excretion of urea. These results indicate that the kidneys, together with the liver, might contribute to the hyperammonaemia caused by valproate.
Ammonia↗
Characteristics of acetaldehyde metabolism in isolated dog, rat and guinea-pig kidney tubules.
The metabolism of acetaldehyde was studied in isolated dog, rat and guinea-pig kidney-cortex tubules. In contrast with previous observations of Cederbaum and Rubin in rat kidney mitochondria (Archs Biochem. Biophys. 179, 46-66 1977) acetaldehyde was found to be metabolized by the tubules at high rates and in a dose-dependent manner at concentrations up to 5-10 mM. At high acetaldehyde concentrations (1-10 mM) acetaldehyde removal was accompanied by a high rate of acetate accumulation which explained most of the acetaldehyde metabolized in dog and guinea-pig but not in rat kidney tubules. These species differences in acetaldehyde metabolism can be explained by the differences in activities of aldehyde dehydrogenase (EC 1.2.1.3) and acetyl-CoA synthetase (EC6.2.1.1), the enzymes involved in renal acetaldehyde metabolism which were measured in the renal cortex of the three species. The acetaldehyde carbon removed and not accounted for by acetate accumulation was completely oxidized to CO2 as demonstrated by the measurement of [U-14C]-acetaldehyde conversion into 14CO2. At "physiological" acetaldehyde concentrations (0.1 and 0.2 mM) acetaldehyde utilization was also concentration-dependent but no acetate accumulation was observed.
Acetaldehyde↗
Metabolism of acetaldehyde in human and baboon renal cortex. Ethanol synthesis by isolated baboon kidney-cortex tubules.
Acetaldehyde (1-20 mM) was metabolized at high rates and in a dose-dependent manner in isolated human and baboon kidney-cortex tubules. Acetaldehyde removal was accompanied by a large accumulation of acetate in both human and baboon tubules. By contrast, a large synthesis of ethanol was observed only in baboon tubules. Consistent with the latter finding, ethanol was found to be metabolized at significant rates in baboon but not human tubules. In the tubules from both species, a significant fraction of the acetaldehyde removed was also completely oxidized to CO2 and H2O. These results suggest that, in both man and baboon, the kidneys participate in the in vivo metabolism of acetaldehyde; they also suggest that, in contrast with the human kidneys, the baboon kidneys contribute to the detoxication of circulating ethanol.
Acetaldehyde↗
Gas chromatographic method for the measurement of sodium valproate utilization by kidney tubules.
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Animals↗
Reabsorption and secretion of alpha-ketoglutarate along the rat nephron: a micropuncture study.
The transport of alpha-ketoglutarate (alpha-KG) across the luminal membrane of the rat nephron was studied by micropuncture and microassay techniques. In normal and acidotic rats, approximately 75% of the filtered alpha-KG was reabsorbed in the proximal tubule and 20% in the pars recta and/or loop of Henle at endogenous plasma concentration of alpha-KG. A progressive elevation to steady-state levels of plasma alpha-KG resulted in a progressive reduction of the fractional reabsorption of alpha-KG in the proximal tubule as well as in a progressive increase in the fractional reabsorption of alpha-KG in the pars recta and/or loop of Henle. At plasma alpha-KG concentration 20-40 times above normal, reabsorption of alpha-KG was found to be limited by a maximal tubular capacity. In alkalotic rats, net secretion of alpha-KG in the early proximal convoluted tubule, net reabsorption in the remainder of the proximal convoluted tubule, and net secretion in the pars recta and/or loop of Henle were observed. These micropuncture data indicate that, depending on the acid-base conditions, net reabsorption or net secretion of alpha-KG may occur in at least two distinct sites along the rat nephron.
Acid-Base Equilibrium↗
Evidence for glutamine utilization by guinea pig renal cortex.
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Ammonia↗
[Effects of aldosterone on renal ammoniagenesis].
The first section of this short review will present our knowledge on the renal production and excretion of ammonia, and the second portion will consider the data currently available concerned with the possible mechanisms whereby aldosterone influences renal ammoniagenesis.
Aldosterone↗
Vasopressin promotes the metabolism of near-physiological concentration of glutamine in isolated rat liver cells.
In isolated rat liver cells, vasopressin, like glucagon, promotes the metabolism of glutamine used at near-physiological concentration (1 mM). These findings indicate that, in vivo, both hormones might participate in the control of hepatic gluconeogenesis and ureogenesis from glutamine.
Animals↗
Lactate, alanine and glutamine metabolism in isolated canine pup liver cells.
The metabolism of lactate, alanine and glutamine was studied in isolated canine liver cells. Lactate proved a better gluconeogenic precursor than alanine and glutamine. Glucose was synthesized at similar rates from both amino acids and ureogenesis from glutamine was double that from alanine. As in isolated rat liver cells, glucose and urea represented the main carbon and nitrogenous end-products of lactate, alanine and glutamine metabolism. Taken with the known levels of hepatic uptake of glutamine and alanine, these findings suggest that in the fasted dog, unlike in the fasted rat, glutamine and not alanine is the main transporter of nitrogen and carbon from muscle to liver for urea synthesis and gluconeogenesis.
Alanine↗