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PubMed2001

Uremic sera contain inhibitors that block digitoxin-valproic acid interaction.

BACKGROUND: Digitoxin and valproic acid show strong binding to serum albumin. Thus, when present simultaneously in serum, digitoxin and valproic acid compete for binding sites. We studied digitoxin-valproic acid interaction in normal and uremic sera. METHODS: Fluorescence polarization immunoassays were used for measuring total digitoxin and total valproic acid concentrations. We used a modified protocol of improved sensitivity to measure free digitoxin concentrations. We supplemented 2 normal and 2 uremic pools with digitoxin and then aliquots of these pools were further supplemented with various concentrations of valproic acid. After incubation at 37 degrees C for 2 hours in a water bath, specimens were allowed to re-equilibrate at room temperature for 20 minutes. Free digitoxin concentrations were measured. We also investigated digoxin-valproic acid interaction using 1 normal and 1 uremic serum pool. RESULTS: We observed significant increases in free digitoxin concentrations in normal sera in the presence of valproic acid. In contrast, we observed a slight decline in free digitoxin concentration in the presence of valproic acid in uremic sera. We speculated that uremic sera contained inhibitors that block digitoxin-valproic acid interaction and identified indoxyl sulfate as an inhibitor. However, another uremic compound, hippuric acid showed no inhibitory effect. Interestingly, we observed no significant interaction between digoxin and valproic acid in either normal or uremic serum pool. This is probably because of poor protein binding of digoxin. CONCLUSION: We conclude that valproic acid significantly displaces digitoxin from protein binding sites in normal serum. However, uremic sera contain inhibitors that block digitoxin-valproic acid interaction.

Anticonvulsants↗
PubMed1988

Displacement by anionic drugs of endogenous ligands bound to albumin in uremic serum.

Impaired binding of anionic drugs to serum albumin in patients with uremia is thought to be due to the accumulation of endogenous substances that bind to albumin. In this study the displacement by the anionic drugs diazepam, warfarin, and salicylic acid, which are known to be representative drugs for the binding sites on the albumin molecule, of several endogenous ligands that bind to albumin in uremic serum was examined. The free fractions of the ligands bound to albumin were separated by ultrafiltration in the presence and the absence of test drugs and assayed by high-performance liquid chromatography. Diazepam displaced indoxyl sulfate (IS), hippuric acid (HA), and indole-3-acetic acid (IAA), and warfarin displaced IS, HA, ISAA, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid from serum albumin. However, salicylic acid did not displace the substance examined. The methods reported here are useful for determining the binding sites of the endogenous ligands on albumin and to clarify the drug-ligand interaction on albumin molecule in uremic serum.

Binding Sites↗
PubMed1998

Elevated free fosphenytoin concentrations in uremic sera: uremic toxins hippuric acid and indoxyl sulfate do not account for the impaired protein binding of fosphenytoin.

Fosphenytoin is a new phosphate ester prodrug of phenytoin. Impaired protein binding of phenytoin in uremia has been extensively documented, which prompted us to investigate the protein binding of fosphenytoin in uremic sera. Also studied was the role of uremic toxins hippuric acid and indoxyl sulfate as potential inhibitor of the protein binding of fosphenytoin because these compounds impair protein binding of phenytoin in uremia. Five serum pools were prepared from normal volunteers and five pools from patients with uremia. None of them received phenytoin. The normal serum pools were diluted with saline to mimic the albumin concentration of uremic pool. Both the diluted normal pool and the uremic pool were supplemented with fosphenytoin; after incubation at room temperature for 30 minutes, total and free fosphenytoin concentrations as phenytoin equivalents were measured using fluorescence polarization immunoassay (Abbott Laboratories; Abbott Park, IL, U.S.A.). The authors observed significantly elevated free fosphenytoin concentration in uremic sera compared with that of normal sera in all cases. Because both normal and uremic sera had the same concentrations of albumin, the elevated free fosphenytoin concentration in uremic sera was not caused by hypoalbuminemia. Both indoxyl sulfate and hippuric acid cause significant displacement of phenytoin from protein binding. In contrast, none caused any displacement of fosphenytoin from protein binding.

Anticonvulsants↗
PubMed2002

Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity.

In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat organic anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited organic anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 microM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, organic anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.

Animals↗
PubMed2003

Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells.

The mechanism that removes homovanillic acid (HVA), an end metabolite of dopamine, from the brain is still poorly understood. The purpose of this study is to identify and characterize the brain-to-blood HVA efflux transporter at the rat blood-brain barrier (BBB). Using the Brain Efflux Index method, the apparent in vivo efflux rate constant of [3H]HVA from the brain, k(eff), was determined to be 1.69 x 10(-2) minute(-1). This elimination was significantly inhibited by para-aminohippuric acid (PAH), benzylpenicillin, indoxyl sulfate, and cimetidine, suggesting the involvement of rat organic anion transporter 3 (rOAT3). rOAT3-expressing oocytes exhibited [3H]HVA uptake (K(m) = 274 micromol/L), which was inhibited by several organic anions, such as PAH, indoxyl sulfate, octanoic acid, and metabolites of monoamine neurotransmitters. Neurotransmitters themselves did not affect the uptake. Furthermore, immunohistochemical analysis suggested that rOAT3 is localized at the abluminal membrane of brain capillary endothelial cells. These results provide the first evidence that rOAT3 is expressed at the abluminal membrane of the rat BBB and is involved in the brain-to-blood transport of HVA. This HVA efflux transport system is likely to play an important role in controlling the level of HVA in the CNS.

Animals↗
PubMed1994

Transport of thyroxine into cultured hepatocytes: effects of mild non-thyroidal illness and calorie restriction in obese subjects.

OBJECTIVE: Inhibitors of cellular T4 transport leading to diminished plasma T3 production have been identified as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and indoxyl sulphate in uraemia and bilirubin and non-esterified fatty acids (NEFA) in critically ill patients with hyperbilirubinaemia. We question whether other factors are responsible for the altered thyroid hormone parameters observed in mild illness and during calorie restriction. PATIENTS: We studied (i) 18 non-uraemic patients with non-thyroidal illness (NTI) (T4 > or = 60, T3 < or = 1.1 and rT3 > or = 0.45 nmol/l) with serum molar ratios of bilirubin:albumin < or = 0.17 and NEFA:albumin < or = 2.6. These molar ratios have been shown to be the minimum ratios which inhibited T4 transport into rat hepatocytes; (ii) four obese euthyroid subjects on 600 kcal/day for 10-14 days. This diet is known to inhibit the unidirectional T4 transport into human liver in vivo. MEASUREMENTS: We measured iodide production from 125I-T4 by incubating rat hepatocytes with 10% human serum. The deiodination of T4 was used as an index of cellular transport of T4 in vivo. RESULTS: The mean iodide production from 125I-T4 by rat hepatocytes in the presence of 10% serum from NTI patients (98 +/- 17%, mean +/- SD) was not significantly different from the normals (100 +/- 9%). Calorie restriction in euthyroid obese subjects resulted in a small but significant reduction (-12%) of iodide production. Calorie restriction increased the total serum NEFA by 91%. CONCLUSIONS: Our study demonstrates that CMPF, indoxyl sulphate, bilirubin and NEFA are not responsible for the inhibition of T4 tissue uptake in patients with mild illness. In addition, studies with calorie restricted obese subjects indicate that high concentration of NEFA during calorie restriction inhibits T4 tissue uptake. This inhibition may partly explain the lower plasma T3 during calorie restriction.

Bilirubin↗
PubMed2004

The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair.

BACKGROUND: Cardiovascular diseases are the major causes of mortality in uremic patients, and the vascular endothelium is dysfunctional in uremia. We hypothesized that uremic retention solutes may be among the factors involved in this endothelial dysfunction. We therefore investigated the in vitro effect of a large panel of uremic retention solutes (guanidino compounds, polyamines, oxalate, myoinositol, urea, uric acid, creatinine, indoxyl sulfate, indole-3-acetic acid, p-cresol, hippuric acid, and homocysteine) on endothelial proliferation. In addition, we tested the effect of uremic solutes that altered proliferation on endothelial wound repair. METHODS: Human umbilical vein endothelial cells (HUVEC) were incubated with uremic retention solutes at concentrations in the range found in uremic patients. Protein-bound uremic solutes were also tested in the presence of 4% human albumin. Then, we determined the effect of each uremic solute on endothelial proliferation by a 5-bromo-2-deoxy-uridine (BrdU) labeling assay. In addition, confluent endothelial monolayers were injured, incubated with uremic solutes that altered endothelial proliferation, and the surface of the wound was measured at different intervals by image analysis. RESULTS: Endothelial proliferation was inhibited by two protein-bound uremic retention solutes: p-cresol and indoxyl-sulfate. Inhibition of endothelial proliferation by p-cresol was dose-dependent. Moreover, p-cresol and indoxyl sulfate decreased endothelial wound repair. The presence of albumin did not affect the inhibitory effect of these solutes on endothelial proliferation, but the decrease in endothelial wound repair was less marked in the presence of albumin. CONCLUSION: We demonstrated that both p-cresol and indoxyl sulfate decrease endothelial proliferation and wound repair. These solutes could play a role in endothelial dysfunction observed in uremic patients.

Apoptosis↗
PubMed2005

Elevation of circulating endothelial microparticles in patients with chronic renal failure.

BACKGROUND: Chronic renal failure patients are at high risk of cardiovascular events and display endothelial dysfunction, a critical element in the pathogenesis of atherosclerosis. Upon activation, the endothelium sheds microparticles, considered as markers of endothelial dysfunction that also behave as vectors of bioactive molecules. AIM: To measure plasma levels of endothelial microparticles (EMPs) in chronic renal failure patients (CRF), either undialyzed or hemodialyzed (HD), and to investigate the ability of uremic toxins to induce EMP release in vitro. METHODS: Circulating EMPs were numerated by flow cytometry, after staining of platelet-free plasma with phycoerythrin (PE)-conjugated anti-CD144 (CD144+ EMP) or anti-CD146 (CD146+ EMP) monoclonal antibodies. Platelet MP (CD41+ PMP), leukocyte MP (CD45+ leukocyte microparticles (LMP)), and annexin-V+ MPs were also counted. In parallel, MPs were counted in supernatant of human umbilical vein endothelial cells incubated with uremic toxins [oxalate, indoxyl sulfate, p-cresol, and homocysteine (Hcy)], at concentrations found in patients. RESULTS AND CONCLUSIONS: CD144+ EMP and CD146+ EMP levels were significantly higher in CRF and HD patients than in healthy subjects. Furthermore, annexin-V+ MPs were elevated in both groups of uremic patients, and CD41+ PMP and CD45+ LMP were increased in CRF and HD patients, respectively. In vitro, p-cresol and indoxyl sulfate significantly increased both CD146+ and annexin-V+ EMP release. Increased levels of circulating EMP in CRF and HD patients represent a new marker of endothelial dysfunction in uremia. The ability of p-cresol and indoxyl sulfate to increase EMP release in vitro suggests that specific uremic factors may be involved in EMP elevation in patients.

Adult↗
PubMed1993

[Purple urine bag syndrome (PUBS) associated with strong alkaline urine].

Mechanisms for purple discoloration of the plastic urine bag in purple urine bag syndrome (PUBS) were investigated. Activities of bacterial indoxyl sulfatase catalyzing the conversion of indoxyl sulfate to indigo (or indirubin) were detected in strong alkaline liquid media but not in normal ones. These enzyme activities were particularly high in simple and combined cultures of Proteus mirabilis and/or Klebsiella pneumoniae. These results suggest that occurrence of PUBS is associated with strong alkaline urine as well as urinary tract infections induced by some species of bacteria with indoxyl sulfatase.

Aged↗
PubMed1995

[Study on purple pigmentation in five cases with purple urine bag syndrome].

We reported five patients with purple urine bag syndrome (PUBS). Four patients had indicanuria, and, in three of them, purple pigmentation was reproduced by inoculating urinary isolates, in the broth with indoxyl sulfate. Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterococcus avium were considered to produce the purple pigment in three patients. However, attempts to reproduce the purple pigment failed in two patients, and one of them did not have indicanuria. These results suggest that indicanuria is not necessarily required for the development of PUBS.

Aged↗
PubMed2004

Effects of uremic toxins on hepatic uptake and metabolism of erythromycin.

Hepatic clearance of erythromycin (Ery) is significantly reduced in patients with end stage renal disease. Since Ery is primarily eliminated via excretion of unchanged drug in the bile, we suspect that this change could be due to the effect of uremic toxins on hepatic uptake and/or efflux transporters. Using rat hepatocytes and microsomes as model proof of concept systems, we examined six uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate (IS), hippuric acid (HA), indole acetic acid (IA), guanidinosuccinic acid (GSA), and indoxyl-beta-D-glucuronide (IG), for their effects on Ery uptake and metabolism. Ery and the metabolite N-demethyl-Ery were measured by liquid chromatography/tandem mass spectrometry. The uptake of Ery by rat hepatocytes was markedly inhibited by rifampin and digoxin, but not by quinidine, suggesting that Oatp2 plays a major role in the uptake of Ery. At 50 microM, CMPF significantly (p < 0.05) reduced hepatocyte accumulation of Ery and N-demethyl-Ery. At higher concentrations (>200 microM), CMPF appears to also inhibit the enzymatic metabolism of Ery. In contrast, IS did not significantly inhibit the hepatocyte uptake of Ery, even at the highest concentration (800 microM) tested, but reduced metabolite generation (p < 0.001). The other uremic toxins, HA, IA, IG, and GSA, did not affect either hepatic uptake or microsomal metabolism of Ery. CMPF, IS, and HA were shown not to inhibit differential P-glycoprotein transport of Ery in cellular systems. Our results suggest that CMPF can directly inhibit the uptake of Ery by inhibiting Oatp2, whereas IS is more likely to inhibit the enzymatic metabolism of Ery.

Animals↗
PubMed1988

Enzymatic degradation of urinary indoxyl sulfate by Providencia stuartii and Klebsiella pneumoniae causes the purple urine bag syndrome.

The etiology of the purple urine bag syndrome (PUBS), in which the urinary catheter bag of some elderly patients develops intense purple coloration, was studied. The purple was found to be a mixture of indirubin dissolved in the plastic and indigo on its surface. Six patients with PUBS were studied, and Providencia stuartii was isolated from the urine of five and Klebsiella pneumoniae was isolated from the urine of one. These strains produced indigo in 7.9 mM indoxyl sulfate-containing agar. One hundred and fifty isolates of 41 species of bacteria were tested for their ability to produce indigo on agar containing indoxyl sulfate, but only 17 of 27 strains of P. stuartii, a single strain of Klebsiella pneumoniae, and Enterobacter agglomerans were positive. All of the indigo-producing bacteria had an indoxyl phosphatase with a pI of 6.4. This enzyme also possessed indoxyl sulfatase activity and was not present in strains that were unable to produce indigo from indoxyl sulfate. We conclude that PUBS results from the decomposition of urinary indoxyl sulfate to indigo and indirubin by bacteria (notably P. stuartii). As elderly catheterized patients often have high urinary indoxyl sulfate levels and colonization of their urinary tract with P. stuartii, the condition is most commonly seen in them.

Bacteriuria↗