Effect of selenium deficiency on tissue taurine concentration and urinary taurine excretion in the rat

The purpose of this study was to determine the effect of selenium deficiency on tissue taurine levels and urinary taurine excretion. Weanling male Sprague-Dawley rats were fed selenium-deficient or selenium-adequate diets for 20 weeks. As selenium deficiency developed, urinary taurine excretion increased in selenium-deficient rats compared to controls. At 12 weeks, the selenium-deficient rats excreted 1.7-fold more taurine than control rats. At the same time plasma glutathione peroxidase was 1.2% of control and plasma glutathione was 226% of control. At 20 weeks, renal taurine was decreased but renal glutathione was increased in selenium-deficient rats compared to controls. Feeding the experimental diet for 6 weeks without methionine supplementation caused a fall in urinary taurine excretion. However, there was no difference between selenium-deficient and control rats. These results indicate that selenium deficiency affects renal handling of taurine in the rat when dietary sulfur amino acids are not restricted.     

Factors affecting formiminoglutamic acid excretion in vitamin B12 deficiency

1. Formiminoglutamic acid, a product of the catabolism of histidine, is excreted in abnormally large amounts in the urines of vitamin B(12)-deficient rats and of vitamin B(12)-deficient sheep; the excretion is reduced to negligible amounts after administration of vitamin B(12). 2. After administration of certain methyl donors to vitamin B(12)-deficient rats or sheep urinary excretion of formiminoglutamic acid is temporarily decreased. 3. Irrespective of the pteroylglutamic acid status of the animals neither vitamin B(12)-deficient rats nor vitamin B(12)-deficient sheep have the ability to deal efficiently with histidine. 4. In sheep, urinary excretion of formiminoglutamic acid is increased after administration of aminopterin; treatment with pteroylglutamic acid restores the ability of the animal to deal with the catabolic products of histidine. 5. The possible functions of vitamin B(12) and methionine in relieving a virtual deficiency of pteroylglutamic acid are discussed.     

The role of histidine in the anemia of folate deficiency

The amino acid histidine is metabolized to glutamic acid in mammalian tissue. Formiminoglutamic acid (FIGLU) is an intermediary in this reaction, and tetrahydrofolic acid is the coenzyme that converts it to glutamic acid. A test for folate deficiency concerns the measurement of urinary FIGLU excretion after a histidine load. It was observed that folate-deficient individuals receiving the histidine for the FIGLU test made hematological response that alleviated the anemia associated with this deficiency. This was unusual in that a biochemical test to determine the deficiency results in a beneficial effect for one aspect of the deficiency. The studies reported in this paper give a metabolic explanation for this phenomenon. Urine was collected for 24 hr from 25 folate-deficient subjects, 10 vitamin B(12)-deficient subjects, and 15 normal controls. Urinary excretion of histidine was a mean of 203 mg with a range of 130-360 mg for the folate-deficient subjects; 51.5 mg with a range of 30-76.6 mg for normal subjects; and 60.0 mg with a range of 32.3-93.0 mg for the vitamin B(12)-deficient subjects. All the folate-deficient subjects subsequently made a hematological response to the histidine administered for the FIGLU test. No hematological response was observed in the vitamin B(12)-deficient individuals. When folic acid was given to folate-deficient subjects who received no histidine, urinary histidine levels returned to normal levels rapidly and this was followed by a hematological response. Others have shown that volunteers fed a histidine-free diet developed anemia. In normal subjects, histidine is excreted much more in the urine than other essential amino acids are. Hemoglobin protein contains 10% histidine. Under normal conditions, dietary histidine can supply sufficient histidine to prevent anemia. When the dietary intake is diminished or the urinary excretion is greatly increased, anemia results. It is concluded that folate deficiency causes histidine depletion through increased urinary excretion of this amino acid. Feeding histidine replenishes tissue levels of histidine, resulting in hemoglobin regeneration. Folic acid administration results in return of histidine to normal urinary levels. Thus, a combination of folic acid histidine would be beneficial for folate deficient individuals.     

Effect of oral methionine and vitamin E on blood lipid peroxidation in vitamin B6 deficient rats

Lipid peroxidation in blood of vitamin B6 deficient rats was significantly increased when compared to pair-fed controls. The observed increased lipid peroxidation in vitamin B6 deficiency was correlated with high levels of lipids, metal ions and low levels of antioxidants, alpha-tocopherol, ascorbic acid and reduced GSH. Supplementation of methionine or vitamin E along with the vitamin B6 deficient diet restored the levels of antioxidants to near normal and also protected against oxidative stress. However plasma TBARS level as well as total lipids were still elevated in M-B6 diet fed rats and normalized in E-B6-d rats.     

Experimental oxalate urolith formation in rats.

Urinary calculi composed of calcium oxalate were produced in male hooded Wistar rats fed a vitamin B6 deficient diet over 16 weeks. This basic diet was modified by doubling the phosphate content or loading with vitamin C or D3 in three treatment groups. The number of rats developing oxalate stones was not altered by the addition of vitamin D3 or phosphate, but there was a significant increase in total weight of stone formed and histological evidence of extensive renal damage in rats on the high vitamin D3 diet. The addition of vitamin C to the vitamin B6 deficient rats resulted in a reduction in the number of rats with uroliths and a fall in urinary oxalate excretion, while similarly loaded vitamin B6 supplemented controls were free of oxalate calculi. It is concluded that the oxalate urolithiasis induced by vitamin B6 deficiency was exacerbated by added vitamin D3 and reduced by vitamin C.     

Carnitine metabolism in the vitamin B-12-deficient rat.

In vitamin B-12 (cobalamin) deficiency the metabolism of propionyl-CoA and methylmalonyl-CoA are inhibited secondarily to decreased L-methylmalonyl-CoA mutase activity. Production of acylcarnitines provides a mechanism for removing acyl groups and liberating CoA under conditions of impaired acyl-CoA utilization. Carnitine metabolism was studied in the vitamin B-12-deficient rat to define the relationship between alterations in acylcarnitine generation and the development of methylmalonic aciduria. Urinary excretion of methylmalonic acid was increased 200-fold in vitamin B-12-deficient rats as compared with controls. Urinary acylcarnitine excretion was increased in the vitamin B-12-deficient animals by 70%. This increase in urinary acylcarnitine excretion correlated with the degree of metabolic impairment as measured by the urinary methylmalonic acid elimination. Urinary propionylcarnitine excretion averaged 11 nmol/day in control rats and 120 nmol/day in the vitamin B-12-deficient group. The fraction of total carnitine present as short-chain acylcarnitines in the plasma and liver of vitamin B-12-deficient rats was increased as compared with controls. When the rats were fasted for 48 h, relative or absolute increases were seen in the urine, plasma, liver and skeletal-muscle acylcarnitine content of the vitamin B-12-deficient rats as compared with controls. Thus vitamin B-12 deficiency was associated with a redistribution of carnitine towards acylcarnitines. Propionylcarnitine was a significant constituent of the acylcarnitine pool in the vitamin B-12-deficient animals. The changes in carnitine metabolism were consistent with the changes in CoA metabolism known to occur with vitamin B-12 deficiency. The vitamin B-12-deficient rat provides a model system for studying carnitine metabolism in the methylmalonic acidurias.     

Inflammation causes tissue-specific depletion of vitamin B<Subscript>6</Subscript>

Previously we observed strong and consistent associations between vitamin B₆ status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B₆ levels. Such strong associations imply that impaired vitamin B₆ status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B₆ tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B₆ during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B₆. The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B₆ excretion. Possible causes of decreased levels of vitamin B₆ are discussed.     

Effects of high salt diets and taurine on the development of hypertension in the stroke-prone spontaneously hypertensive rat

Summary. Taurine is present in high concentrations in mammalian tissues and has been implicated in cardiovascular control mechanisms. The aim of the present study was to evaluate the ability of taurine to attenuate salt-induced elevations in blood pressure and markers of damage to the kidney and cardiovascular system in stroke prone spontaneously hypertensive rats (SPSHR). Male SPSHR (6 weeks old) were placed on high salt diets that contained 1% (w/w) NaCl added to their normal chow for 84 days and then were switched to 3% added NaCl for the remaining 63 days of the study. SPSHR was given 1.5% taurine in the drinking water (n = 8), a taurine free diet (n = 8) or normal chow (n = 8). A final control group (n = 6) was not given high salt diets. High salt diets caused an acceleration in the development of hypertension in all groups. Taurine supplementation reduced ventricular hypertrophy and decreased urinary excretion of protein and creatinine. The taurine free diet did not alter serum or urinary excretion of taurine, but did result in elevated urinary nitrogen excretion, increased serum cholesterol levels, and impaired performance in a spatial learning task. Alterations in dietary taurine intake did not alter urinary or serum electrolytes (Na⁺, K⁺), but taurine supplementation did attenuate a rise in serum calcium seen with the high salt diets. Urinary excretion (μg/24 h) of epinephrine and dopamine was significantly reduced in SPSHR given 1% NaCl in the diet, but this effect was not seen in SPSHR on taurine free or supplemented diets. Taurine supplementation showed cardioprotective and renoprotective effects in SPSHR given high salt diets. Received April 12, 1999/Accepted September 13, 1999     

Changes in urinary taurine and hypotaurine excretion after two-thirds hepatectomy in the rat

Summary This study followed the time course of urinary taurine and hypotaurine excretion after two-thirds hepatectomy in rats. The excretion of both taurine and hypotaurine was elevated during 18th following the hepatectomy, with maximal excretion during the first 6h. Twelve and 24h after partial hepatectomy, the hepatic hypotaurine concentration was increased but liver taurine did not differ significantly from controls. No changes were observed in hypotaurine and taurine concentrations of heart, kidney, lung, muscle tissue and spleen. We postulate that partial hepatectomy induces a rapid increase of hepatic (hypo)taurine synthesis from precursor amino acids. The increased (hypo)taurine concentrations spill over into urine.     

Taurine mobilizing effects of beta alanine and other inhibitors of taurine transport

Oral administration of a 3% beta alanine solution in the drinking water was as effective in increasing urinary taurine excretion and decreasing tissue taurine levels in rats as subcutaneous or intraperitoneal administration. Beta alanine was more effective in reducing tissue taurine levels in rats and guinea pigs than in mice. Other inhibitors of taurine transport were compared with beta alanine for their ability to reduce tissue taurine levels. Taurocyamine, the guanidino analogue of taurine, was less effective in rats than beta alanine in reducing taurine levels in gastrocnemius but more effective in reducing brain taurine levels, whereas the homologue of beta alanine, GABA, was relatively ineffective in either mice or rats.     

Taurine: Protective properties against ethanol-induced hepatic steatosis and lipid peroxidation during chronic ethanol consumption in rats

Summary Alcohol was administered chronically to female Sprague Dawley rats in a nutritionally adequate totally liquid diet for 28 days. This resulted in hepatic steatosis and lipid peroxidation. Taurine, when co-administered with alcohol, reduced the hepatic steatosis and completely prevented lipid peroxidation. The protective properties of taurine in preventing fatty liver were also demonstrated histologically. Although alcohol was found not to affect the urinary excretion of taurine (a non-invasive marker of liver damage), levels of serum and liver taurine were markedly raised in animals receiving alcohol + taurine compared to animals given taurine alone. The ethanol-inducible form of cytochrome P-450 (CYP2E1) was significantly induced by alcohol; the activity was significantly lower than controls and barely detectable in animals fed the liquid alcohol diet containing taurine. In addition, alcohol significantly increased homocysteine excretion into urine throughout the 28 day period of ethanol administration; however, taurine did not prevent this increase. There was evidence of slight cholestasis in animals treated with alcohol and alcohol + taurine, as indicated by raised serum bile acids and alkaline phosphatase (ALP). The protective effects of taurine were attributed to the potential of bile acids, especially taurine conjugated bile acids (taurocholic acid) to inhibit the activity of some microsomal enzymes (CYP2E1). Thesein vivo findings demonstrate for the first time that hepatic steatosis and lipid peroxidation, occurring as a result of chronic alcohol consumption, can be ameliorated by administration of taurine to rats.     

Melatonin and taurine reduce early glomerulopathy in diabetic rats

Oxidative stress occurs in diabetic patients and experimental models of diabetes. We examined whether two antioxidants, melatonin and taurine, can ameliorate diabetic nephropathy. Enhanced expression of glomerular TGF-beta1 and fibronectin mRNAs and proteinuria were employed as indices of diabetic nephropathy. Experimental diabetes was induced by intravenous injection of streptozotocin 50 mg/kg. Two days after streptozotocin, diabetic rats were assigned to one of the following groups: i) untreated; ii) melatonin supplement by 0.02% in drinking water; or iii) taurine supplement by 1% in drinking water. Four weeks after streptozotocin, diabetic rats (n = 6: plasma glucose 516+/-12 mg/dl) exhibited 6.1 fold increase in urinary protein excretion, 1.4 fold increase in glomerular TGF-beta1 mRNA, 1.7 fold increase in glomerular fibronectin mRNA, 2.2 fold increase in plasma lipid peroxides (LPO), and 44 fold increase in urinary LPO excretion above the values in control rats (n = 6: plasma glucose 188+/-14 mg/dl). Chronic administration of melatonin (n = 6) and taurine (n = 6) prevented increases in glomerular TGF-beta1 and fibronectin mRNAs and proteinuria without having effect on blood glucose. Both treatments reduced lipid peroxidation by nearly 50%. The present data demonstrate beneficial effects of melatonin and taurine on early changes in diabetic kidney and suggest that diabetic nephropathy associated with hyperglycemia is largely mediated by oxidative stress.     

Free Radical-Induced Liver Injury. I. Effects of Dietary Vitamin E Deficiency on Triacylglycerol Level and its Fatty Acid Profile in Rat Liver

Effects of dietary vitamin E deficiency on the fatty acid compositions of total lipids and phospholipids were studied in several tissues of rats fed a vitamin E-deficient diet for 4, 6, and 9 months. No significant differences were observed between the vitamin E deficiency and controls except in the fatty acid profiles of liver total lipids. Triacylglycerol (TAG) accumulation was found in the liver of rats fed a vitamin E-deficient diet. The levels of TAG-palmitate and -oleate increased particularly in the liver from such animals. The fatty acid compositions of hepatic phospholipids were not affected by the diet. Increased TAG observed in the liver of rats fed a vitamin E-deficient diet was restored to normal when the diet was supplemented with 20 mg α-tocopheryl acetate/kg diet. These findings indicate that dietary vitamin E deficiency causes TAG accumulation in the liver and that the antioxidant, vitamin E, is capable of preventing free radical-induced liver injury.     

Taurine supplementation improves the utilization of sulfur-containing amino acids in rats continually administrated alcohol

The main purpose of this study was to evaluate changes in brain sulfur-containing amino acid (SCAA) metabolism to determine whether taurine intervened under continuous alcohol intake. We fed 80 male Sprague-Dawley rats 30% alcohol-containing water for 4 weeks. Eighty animals were divided into two groups (with or without 2 g/kg body weight taurine supplementation), and five were killed every week in each group for monitoring SCAA changes in the brain, liver, kidneys and heart. Results indicated that the plasma alcohol concentration increased from Weeks 1-4; however, animals with taurine supplementation showed a lower plasma concentration of ethanol in Week 2. As to SCAA concentrations, cysteine and taurine were both lower after a week of alcohol ingestion in the brain and plasma; the same declining trend was shown in the liver in Week 2. In contrast, plasma and hepatic concentrations of homocysteine were elevated in Week 2, and the plasma S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio also decreased in Week 1. Furthermore, the key cofactor of transsulfuration, pyridoxal-5'-phosphate, significantly declined in the plasma after a week of the ethanol intervention, whereas an increase was observed in brain tissue. Under taurine supplementation, some recoveries were shown by delaying taurine depletion to Week 2, increasing the SAM/SAH ratio and elevating plasma and brain levels of vitamin B6 in Week 2. In conclusion, daily consumption of 30% alcohol interfered with SCAA metabolism, thus decreasing taurine's role in neurotransmission. The possible mechanism involved might be that ethanol interrupts the production of cysteine, which is the upstream SCAA of taurine, thus decreasing the homocysteine level. Additionally, taurine supplementation delayed this process.     

An estimation of the parathyroid hormone secretion rate in vitamin D deficient rats.

In an attempt to define the rate of endogenous secretion of parathyroid hormone in vitamin D deficiency, graded amounts of hormone were infused constantly into vitamin D deficient and vitamin D fed acutely thyroparathyroidectomized rats in a perfusion balance study. The dose of hormone needed to compensate for acute thyroparathyroidectomy was estimated. Serum levels of calcium and phosphorus, renal clearances of phosphorus and urinary excretion of cyclic AMP, each determined 16 hr after the surgery, were employed as parameters of the hormone effect. It was concluded that, in the condition of the perfusion balance study, the secretion rate of parathyroid hormone was 5.1-8.6 USP u/hr in the vitamin D deficient animals compared with 0.81-0.84 USP u/hr in the control.     

Cobalamin deficiency results in severe metabolic disorder of serine and threonine in rats.

Dietary cobalamin (vitamin B12; Cbl) deficiency caused significant increases in plasma serine, threonine, glycine, alanine, tyrosine, lysine and histidine levels in rats. In particular, the serine and threonine levels were over five and eight times, respectively, higher in the Cbl-deficient rats than those in the sufficient controls. In addition, some amino acids, including serine and threonine, were excreted into urine at significantly higher levels in the deficient rats. When Cbl was supplemented into the deficient rats for 2 weeks, in coincidence with the disappearance of the urinary excretion of methylmalonic acid (an index of Cbl deficiency), the plasma serine and threonine levels were normalized. These results indicate that Cbl deficiency results in metabolic disorder of certain amino acids, including serine and threonine. The expression level of hepatic serine dehydratase (SDH), which catalyzes the conversion of serine and threonine to pyruvate and 2-oxobutyrate, respectively, was significantly lowered by Cbl deficiency, even though Cbl does not participate directly in the enzyme reaction. The SDH activity in the deficient rats was less than 20% of that in the sufficient controls, and was normalized 2 weeks after the Cbl supplementation. It is thus suggested that the decrease of the SDH expression relates closely with the abnormalities in the plasma and urinary levels of serine and threonine in the Cbl-deficient rats.     

SOME EFFECTS OF DIETARY VITAMIN B6 DEFICIENCY AND 4-DEOXYPYRIDOXINE ON γ-AMINOBUTYRIC ACID METABOLISM IN RAT BRAIN

Abstract— Investigations of the respective effects of dietary vitamin B₆ deficiency and 4-deoxypyridoxine (a vitamin B₆ antagonist) on GABA metabolism in rat brain have been carried out. No convulsions were observed in rats subjected to either treatment. GABA levels were lowered by both treatments, the greatest diminutions being found with the dietary deficiency. Glutamic acid decarboxylase activity was reduced under both conditions, but the loss of activity in the B₆ deficiency experiments could be attributed to cofactor depletion, whereas in the deoxypyridoxine experiments the loss of activity appears to be due to lower levels of available apoenzyme. The activity of GABA-transaminase was not affected by deoxypyridoxine treatment and only moderately reduced in the B.5 deficient animals.     

Hoe 140 abolishes the blood pressure lowering effect of taurine in high fructose-fed rats

Summary. High fructose feeding induces moderate increases in blood pressure of normal rats, associated with hyperinsulinemia, insulin resistance and impaired glucose tolerance. Increased vascular resistance, and sodium retention have been proposed to contribute to the blood pressure elevation in this model. Taurine, a sulphur-containing amino acid has been reported to have antihypertensive and antinatriuretic actions. In addition, taurine is shown to increase the excretion of nitrite and kinin availability and hence would be expected to improve the vascular tone. In the present study, the involvement of kinins in the blood pressure lowering effect of taurine was investigated by coadministration of Hoe 140, a kinin B₂ receptor antagonist along with taurine. The effects of taurine on plasma and urinary concentrations of sodium and tissue kallikrein activity were studied in high fructose-fed rats. Fructose-fed rats had elevated blood pressure and decreased levels of sodium in urine. Treatment with 2% taurine in drinking water prevented the blood pressure elevation and coadministration of Hoe 140 abolished this effect of taurine in high fructose-fed rats. The findings confirm the antinatriuretic action of taurine and also suggest a role for the kinins in the mechanism of taurine action in diet-induced hypertension.     

Cobalamin deficiency results in severe metabolic disorder of serine and threonine in rats

Dietary cobalamin (vitamin B12; Cbl) deficiency caused significant increases in plasma serine, threonine, glycine, alanine, tyrosine, lysine and histidine levels in rats. In particular, the serine and threonine levels were over five and eight times, respectively, higher in the Cbl-deficient rats than those in the sufficient controls. In addition, some amino acids, including serine and threonine, were excreted into urine at significantly higher levels in the deficient rats. When Cbl was supplemented into the deficient rats for 2 weeks, in coincidence with the disappearance of the urinary excretion of methylmalonic acid (an index of Cbl deficiency), the plasma serine and threonine levels were normalized. These results indicate that Cbl deficiency results in metabolic disorder of certain amino acids, including serine and threonine. The expression level of hepatic serine dehydratase (SDH), which catalyzes the conversion of serine and threonine to pyruvate and 2-oxobutyrate, respectively, was significantly lowered by Cbl deficiency, even though Cbl does not participate directly in the enzyme reaction. The SDH activity in the deficient rats was less than 20% of that in the sufficient controls, and was normalized 2 weeks after the Cbl supplementation. It is thus suggested that the decrease of the SDH expression relates closely with the abnormalities in the plasma and urinary levels of serine and threonine in the Cbl-deficient rats.     

Effect of glucose-cysteine adduct as a cysteine prodrug in rats

Summary Effect of intraperitoneal administration (5 mmol/kg of body weight) of glucose- cysteine adduct (glc-cys) as a cysteine prodrug in rat tissues was studied. Cysteine levels in liver and kidney increased to 1.08 and 1.98mol per g or ml, respectively, at 2h after the administration. GSH levels did not change substantially. However, when glc-cys was injected to rats treated with diethyl maleate, a GSH-depleting agent, the decreased GSH levels were restored rapidly. The recoveries in liver and kidney were 72% at 1h and 66% at 2h, respectively, after glc-cys administration. Metabolism of glc-cys was assessed by urinary excretion of glc-cys, sulfate and taurine. Average excretion of glc-cys was 2.86mmol/kg/24h after glc-cys administration. Increased excretions of sulfate and taurine were 0.77 and 0.14mmol/kg/24h, respectively. Data show that, although glc-cys excretion was relatively rapid, glc-cys was effectively utilized for GSH synthesis in GSH-depleted tissues.