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At least 91 records · Page 5Linked to original sources
PubMed1983

The effects of saccharin on the metabolism of dietary tryptophan to indole, a known cocarcinogen for the urinary bladder of the rat.

Adult male rats were fed diets containing 0 to 10% saccharin, 2% tryptophan, or 2% tryptophan plus 5% saccharin ad libitum for 1 to 2 months. Saccharin produced a dose-related increase in the urinary excretion of indican which is the main metabolite of indole. The renal clearances of both indican and saccharin were reduced at high plasma concentrations (200 to 300 micrograms/ml) of saccharin, suggesting saturation of renal tubular secretion. The increased amounts of indican in the urine, and of indole in the cecum arose from accumulation of protein and tryptophan in the cecum rather than an increase in the enzyme tryptophanase which metabolizes tryptophan to indole. The high levels of protein in the ceca of rats fed saccharin-containing diets were associated with a dose-related increase in the weight of the contents and wall of the cecum. Administration of 2% tryptophan in the diet increased significantly the amounts of tryptophan in the cecum and in plasma, but produced only small increases in the size of the cecum, the amount of indole present, and the excretion of indican. The effects of saccharin and tryptophan were additive. These effects are consistent with saccharin having a major effect on protein digestion in the intestine such that increased amounts of tryptophan are available in the cecum for microbial metabolism to indole. The greater formation of indole and excretion of indican in the urine suggest that saccharin increases the catabolism of dietary tryptophan to metabolites with known cocarcinogenic activity toward the rat bladder.

Animals↗
PubMed1989

Comparison of the bladder response to indole and sodium saccharin ingestion by male rats.

To ascertain whether the bladder mass increase and epithelial hyperplasia induced by 5% dietary sodium saccharin (NaS) in short-term experiments with rats are caused by increased urinary excretion of indican associated with this treatment, the responses of the urine and bladder induced by 1.5% indole (Id) ingestion were compared with those induced by 5% NaS and 1.5% Id + 5% NaS. Id and NaS, when fed alone, produced equivalent increases in bladder mass and both compounds induced epithelial hyperplasia, but Id ingestion was associated with much greater urinary indican excretion (5 mg/g diet ingested) than was NaS (0.3 mg/g diet ingested). When Id and NaS were ingested together, the bladder mass increase was additive, but the epithelial hyperplasia was not exacerbated over that observed with each alone, and the urinary indican was equivalent to that produced by Id alone. These findings suggest that a high level of urinary indican excretion is associated with an increase in bladder mass and epithelial hyperplasia (Id treatment) but indicate that the relatively low urinary indican level obtained by NaS feeding alone is unlikely to be responsible for the bladder responses noted with this compound.

Animals↗
PubMed2005

Removal of P-cresol sulfate by hemodialysis.

Protein-bound solutes are poorly cleared by dialysis. Among the most extensively studied of these solutes is p-cresol, which has been shown to be toxic in vitro. This study examined the form in which p-cresol circulates and quantified its removal by hemodialysis. HPLC analysis of plasma from hemodialysis patients contained a peak whose mobility corresponded to synthetic p-cresol sulfate (PCS) but no detectable unconjugated p-cresol. Treatment with sulfatase resulted in recovery of this peak as p-cresol, confirming its identity. Subsequent studies compared the removal of PCS and another protein-bound solute, indican, to the removal of urea during clinical hemodialysis treatments. PCS and indican were 94 +/- 1% and 93 +/- 2% bound to plasma protein, respectively. Protein-binding caused a predictable decrease in measured dialytic clearance, which averaged 20 +/- 4 ml/min for PCS and 25 +/- 5 ml/min for indican as compared with 260 +/- 20 ml/min for urea. Volumes of distribution for the protein-bound solutes were greater than the plasma volume, averaging 15 +/- 7 L for PCS and 14 +/- 3 L for indican as compared with 37 +/- 7 for urea. Solute reduction ratios were 20 +/- 9% for PCS, 30 +/- 7% for indican, and 69 +/- 5% for urea. We conclude that p-cresol circulates in the form of its sulfate conjugate, PCS. PCS is poorly removed by hemodialysis because its clearance is limited by protein binding and the ratio of its volume of distribution to its clearance is high.

Adult↗
PubMed1987

The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man.

Low dietary levels of sodium saccharin (0-2%) fed to male rats for 6 weeks produced a dose-related increase in the urinary excretion of p-cresol, a major microbial metabolite of tyrosine. Some animals fed higher levels of saccharin (5-7.5%) for 6 weeks excreted increased amounts of p-cresol, but many excreted negligible amounts so that the overall dose-response relationship was bell shaped. After 20 weeks of exposure, all rats in the higher dose groups showed increased p-cresol excretion and by 26 weeks the 7.5% saccharin group showed a 36-fold increase over animals fed the 0% saccharin diet. The urinary excretion of phenol, another microbial amino acid metabolite, was constant in animals fed dietary levels of saccharin below 2% for 6 weeks, but was virtually abolished at higher levels. The excretion of indican (formed from indole, a microbial metabolite of tryptophan) was increased by saccharin in a dose-related fashion at all time points, but showed only a 3-fold increase at 7.5% compared with the 0% group. p-Cresol may therefore prove more sensitive than indican as an indicator of altered microbial metabolism due to saccharin. In a separate study the effect of 7.5% saccharin on p-cresol and indican excretion was shown to be largely reversible and the excretion of phenol increased rapidly when saccharin was withdrawn from the diet. Chronic saccharin administration to man at high doses (1 g/day for 4 weeks) had no perceptible effect on the excretion of these three metabolites.

Amino Acids↗
PubMedDate not supplied

The microbial metabolism of tryptophan in rats fed a diet containing 7.5% saccharin in a two-generation protocol.

Sodium saccharin was fed at 7.5% in the diet to rats in a two-generation protocol. Saccharin-treated animals in both generations showed increased urinary excretion of indican. During lactation, the pups of saccharin-fed dams were exposed to elevated levels of indican via the milk. Establishment of the gut flora in pups at weaning in the presence of saccharin was associated with increased caecal size and caecal protein, decreased caecal tryptophanase activity, and increased urine volume and urinary indican excretion. Pups from dams fed saccharin from birth only, showed more-variable responses during the first weeks of life than pups from dams fed saccharin from before conception, due to variations in tryptophanase activity. The various biochemical and physiological changes were detected soon after the pups were weaned, and were found equally in both males and females. After adjustment for body weight, the changes detected were greatest during the first month after weaning.

Animals↗
PubMedDate not supplied

The effect of saccharin on the microbial metabolism of tryptophan in man.

The microbial catabolism of tryptophan to indole has been studied in 15 human subjects by analysis of the daily urinary excretion of indican (potassium indoxylsulphate) before, during and after chronic saccharin ingestion. The daily excretion of indican during a 3-wk control period showed marked inter- and intra-subject variability. Analysis of the urinary excretion of saccharin during chronic administration demonstrated good compliance for both saccharin ingestion and urine collection. The urinary excretion of indican was not increased significantly by the ingestion of saccharin (1 g/day as divided doses with meals) for one month. These findings are consistent with epidemiology studies which show the absence of a consistent excess risk of cancer of the urinary bladder in humans ingesting saccharin as a food additive.

Adult↗
PubMed1996

Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis.

The plasma levels of phenol, p-cresol, and indican are markedly increased in uremic patients, and cannot be efficiently reduced by hemodialysis. Such uremic toxins, which are produced in the intestine as bacterial putrefactive metabolites, accumulate to a great degree in the feces of hemodialysis patients. Oral administration of Lebenin, a preparation consisting of antibiotic-resistant lactic acid bacteria, reduced the levels of fecal putrefactive metabolites to levels comparable with those of healthy subjects. Moreover, the plasma level of indican also significantly decreased in these Lebenin-treated patients. An analysis of the fecal microflora revealed that a disturbed composition of the microflora characterized by an overgrowth of aerobic bacteria is restored to normal by oral administration of Lebenin in hemodialysis patients. These results thus demonstrate that oral administration of lactic acid bacteria in uremic patients is effective in reducing the levels of uremic toxins, especially that of indican, in the blood by inhibiting bacterial production by means of correcting the intestinal microflora.

Administration, Oral↗
PubMed2000

Glycoside binding and translocation in Na(+)-dependent glucose cotransporters: comparison of SGLT1 and SGLT3.

Using cotransporters as drug delivery vehicles is a topic of continuing interest. We examined glucose derivatives containing conjugated aromatic rings using two isoforms of the Na(+)/glucose cotransporter: human SGLT1 (hSGLT1) and pig SGLT3 (pSGLT3, SAAT1). Our studies indicate that there is similarity between SGLT1 and SGLT3 in the overall architecture of the vestibule leading to the sugar-binding site but differences in translocation pathway interactions. Indican was transported by hSGLT1 with higher affinity (K(0.5) 0.06 mm) and 2-naphthylglucose with lower affinity (K(0.5) 0. 5 mm) than alpha-methyl-d-glucopyranoside (alpha MDG, 0.2 mm). Both were poorly transported (maximal velocities, I(max), 14% and 8% of alpha MDG). Other compounds were inhibitors (K(i)s 1-13 mm). In pSGLT3, indican and 2-naphthylglucose were transported with higher affinity than alpha MDG (K(0.5)s 0.9, 0.2 and 2.5 mm and relative I(max)s of 80, 25 and 100%). Phenylglucose and arbutin were transported with higher I(max)s (130 and 120%) and comparable K(0. 5)s (8 and 1 mm). Increased affinity of indican relative to alphaMDG suggests that nitrogen in the pyrrole ring is favorable in both transporters. Higher affinity of 2-naphthylglucose for pSGLT3 than hSGLT1 suggests more extensive hydrophobic/aromatic interaction in pSGLT3 than in hSGLT1. Our results indicate that bulky hydrophobic glucosides can be transported by hSGLT1 and pSGLT3, and discrimination between them is based on steric factors and requirements for H-bonding. This provides information for design of glycosides with potential therapeutic value.

Animals↗