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At least 1,621 records · Page 90Linked to original sources
PubMed1992

Acute renal toxicity of thiabendazole (TBZ) in ICR mice.

The acute toxic effects of thiabendazole [2-(4'-thiazolyl)benzimidazole; TBZ] on the kidneys of ICR mice were investigated. The mice were given 0, 250, 500 or 1000 mg TBZ/kg body weight by gavage (using olive oil as a vehicle), and the kidneys were subjected to pathological examination at 1, 3, 5 or 24 hr after dosing. Gross findings were slight enlargement and the presence of whitish areas (white maculae) in kidneys of treated mice at 3, 5 or 24 hr after dosing. Histological findings were desquamation of degenerated cells in proximal tubules of treated mice at 1 hr. Dilation of proximal, distal and collecting tubules was apparent in treated mice at 3, 5 and 24 hr. TBZ-induced renal injury was reduced by pretreatment with inducers of the microsomal monooxygenase system (sodium phenobarbital, beta-naphthoflavone and 3-methylcholanthrene) and were enhanced by pretreatment with inhibitors of that system (2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride and piperonyl butoxide). The concentration of TBZ in blood at 1 or 5 hr after dosing was lower in mice pretreated with microsomal monooxygenase system inducers and was higher in those pretreated with the inhibitors, than in those given TBZ alone. These results suggest that TBZ-induced renal injury may be attributable to the parent compound rather than its metabolites. Measurement of organic ion uptake into renal slices revealed significant depression of [1-14C]tetraethylammonium bromide (TEA) uptake in treated mice at 1 or 5 hr, whereas uptake of p-[glycyl-2-3H]aminohippurate (PAH) was not depressed at 1 or 5 hr after dosing. The reduction in uptake of TEA is interpreted as the result of competitive suppression of the tubular transport of TEA by TBZ. TBZ-induced renal injury was reduced by organic cation transport inhibitors [N'-methylnicotinamide (NMN) or thiamine] but not by organic anion transport inhibitor [p-(dipropylsulphamyl)benzoic acid probenecid], suggesting that the reduction of TBZ-induced renal injury is the result of competitive suppression of the tubular transport of TBZ by NMN or thiamine.

Administration, Oral↗
PubMed1995

Protective effect of metallothionein on intracellular pH changes induced by cadmium.

In order to gain further insight into the protective mechanism of metallothionein (MT) against Cd cytotoxicity, the effects of in vivo Zn- or Cd-pretreatment on the cytotoxicity and alteration in cellular pH induced by Cd were examined in isolated rat hepatocytes and testicular Leydig cells. These pretreatments both induced the synthesis of MT in the hepatocytes, but not in the Leydig cells. Both pretreatments alleviated Cd cytotoxicity in the hepatocytes. Cd- or Zn-pretreatment was also effective in preventing Cd-induced cellular acidification in hepatocytes but neither pretreatment was effective in Leydig cells. In fact, Cd-pretreatment stimulated acidification in Leydig cells. Exposure in vitro of hepatocytes from untreated rats to probenecid, an inhibitor of HCO3-/Cl- exchange, also ameliorated Cd-induced cellular acidification, suggesting an involvement of HCO3-/Cl- exchange in the preventive action of MT against Cd-induced acidification. These results suggest that Cd cytotoxicity in various cells may be initiated by alterations in plasma membrane ion transport systems such as the HCO3-/Cl- exchange and consequential cellular acidification. Induction of MT, therefore, may prevent Cd cytotoxicity, at least in rat hepatocytes, by preventing an alteration in ion transport at the plasma membrane as well as by intracytoplasmic binding of the metal molecules.

Animals↗
PubMed1986

Efflux of cyclic guanosine 3',5'-monophosphate from cerebellar slices stimulated by L-glutamate or high K+ or N-methyl-N'-nitro-N-nitrosoguanidine.

The efflux of cyclic guanosine 3',5'-monophosphate (cGMP) was studied from rat cerebellar slices which were stimulated by L-glutamate (1 mM), or by depolarizing concentrations of K+ (60 mM) or by the nitroso compound, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Via different mechanisms these agents stimulated cGMP synthesis producing several fold elevation of the cGMP content of the tissue slices. Simultaneously with the elevation of the intracellular (intra slice) concentrations of cGMP, a temperature-and time-dependent efflux of cGMP into the medium took place. This efflux was maximal at 5 min and could be inhibited by the known inhibitor of anion transport, probenecid, in a concentration-dependent manner. The results suggest the presence of an efflux system for cGMP, which may participate together with the well-characterized 3',5'-cyclic nucleotide phosphodiesterases in reduction of elevated cGMP levels.

Animals↗
PubMed1994

Effect of active transport on distribution and concentration gradients of [3H]benzylpenicillin in the cerebrospinal fluid.

After application of [3H]benzylpenicillin ([3H]BP) in lateral brain ventricle in dogs, the distribution of [3H]BP to contralateral ventricle and cisterna magna was much higher when its active transport from cerebrospinal fluid (CSF) was blocked by probenecid than under control conditions. Analysis of [3H]BP concentrations in both lateral ventricles and cisterna magna over time indicates that active transport restricts distribution of substances along CSF spaces and contributes to the maintenance of their concentration gradients between CSF compartments. This suggests that biochemical changes in a part of the brain and the adjacent CSF compartment may not be reflected into remote compartments of CSF such as lumbar CSF if substances in question are removed from CSF by active transport.

Animals↗
PubMed1988

A membrane transporter mediates access of uridine 5'-diphosphoglucuronic acid from the cytosol into the endoplasmic reticulum of rat hepatocytes: implications for glucuronidation reactions.

Hepatic glucuronidation of a wide variety of substrates is catalyzed by the membrane-bound UDP-glucuronosyltransferases. Uridine 5'-diphosphoglucuronic acid (UDP-GlcUA) is the essential cosubstrate for all UDP-glucuronosyltransferase-mediated reactions. The mechanism by which this bulky, hydrophilic nucleotide-sugar is transported from the cytosol (where it is synthesized) to its binding site(s) on the enzyme is unknown. To determine whether a membrane carrier mediates the access of UDP-GlcUA into the endoplasmic reticulum, the transport of uridine 5'-diphospho-D-[U-14C]glucuronic acid into vesicles of rough and smooth endoplasmic reticulum isolated from rat liver was investigated at 38 degrees C using a rapid filtration technique. Uptake of UDP-GlcUA by both rough and smooth vesicles was extremely rapid (linear for only 10-20 s) and temperature-dependent (negligible at 4 degrees C). UDP-GlcUA uptake was saturable, and similar kinetic parameters were obtained for rough and smooth vesicles (Km 1.9 microM, Vmax 443 pmol/mg protein per min, and Km 1.3 microM, Vmax 503 pmol/mg protein per min, respectively). The uptake of UDP-GlcUA also exhibited a high degree of specificity, since many related compounds, including UMP, UDP and UDP-Glc, did not influence uptake. In addition, the non-penetrating inhibitors of anion transport, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and probenecid, markedly inhibited UDP-GlcUA uptake. Finally, osmotic modulation of the intravesicular volume did not affect total uptake of UDP-GlcUA by membrane vesicles at equilibrium, indicating that this nucleotide-sugar is transported into the membrane rather than the intravesicular space. Collectively, these data provide direct evidence for a specific, carrier-mediated uptake process, which transports UDP-GlcUA from the cytosol into the endoplasmic reticulum of hepatocytes. This UDP-GlcUA transporter may be involved in the regulation of hepatic glucuronidation reactions.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons.

The effects of extracellularly applied membrane-permeant Ca2+ chelators on field excitatory postsynaptic potentials were determined in the hippocampal CA1 region of rat brain slices. Field excitatory postsynaptic potentials in slices perfused with 0.05-50 microM bis-(-O-aminophenoxy)-ethane-N,N,N,N,-tetraacetic acid acetoxymethyl (BAPTA-AM) for 15 min were reversibly attenuated by 10-45% in a concentration-dependent manner. Attenuation occurred earlier at higher concentrations of BAPTA-AM, thus indicating that the rate of accumulation of BAPTA salt was concentration dependent. Antidromically evoked responses and presynaptic volleys were unaffected by BAPTA-AM. Attenuation of the field excitatory postsynaptic potentials by BAPTA-AM was temporarily eliminated by repetitive stimulation at 1 Hz, suggesting saturation of the chelator's Ca(2+)-binding capacity. The amplitude of field excitatory postsynaptic potentials was unaffected by similar applications of 5'5-dinitro-BAPTA-AM, a low Ca(2+)-affinity BAPTA analogue, and EGTA-AM (5 or 50 microM), a chelator with slow Ca(2+)-binding kinetics, suggesting a dependence of the BAPTA-AM effect on fast Ca2+ binding and high Ca2+ affinity. BAPTA-AM concentrations as low as 0.05 microM were effective provided application was prolonged to 40 min. Probenecid (1 mM), an anion transport inhibitor, accelerated the onset and significantly enhanced the BAPTA-mediated synaptic attenuation caused by low concentrations of BAPTA-AM. These data show that even very low extracellular concentrations of BAPTA-AM can profoundly affect synaptic transmission provided that sufficient chelator accumulates presynaptically. The effectiveness of BAPTA-AM can be increased by procedures which inhibit chelator extrusion.

Animals↗
PubMed1987

Chronic cocaine administration decreases dopamine synthesis rate and increases [3H] spiroperidol binding in rat brain.

Chronic administration of cocaine HCl (10 mg/kg, IP, every 12 hours for 10 consecutive days) resulted in a significantly decreased rate of accumulation of 3,4-dihydroxyphenylalanine following decarboxylase inhibition (-27 to -33%) and of homovanillic acid following probenecid treatment (-25 to -34%) in rat striatum, limbic forebrain and midbrain. In addition, the Bmax for [3H]-spiroperidol receptor binding was significantly increased (+24 to +36%) in these brain regions following chronic cocaine administration. These changes were observed 60 days following termination of the chronic cocaine treatment regimen. These data suggest that cocaine produces long-term, if not permanent, effects on central dopamine synthesis.

Animals↗
PubMed1990

Absorption of methylmercury compounds from rat intestine.

Intestinal absorption of methylmercury complexed with non-protein sulfhydryl compounds (NPSHs) as occurs in bile was studied by means of direct injection of mercury compounds into ligated intestinal segments of rats. The extent of absorption of methylmercury-cysteinylglycine (MM-CysGly) was similar to that of methylmercury-cysteine (MM-Cys) and 1.5 times larger than that of methylmercury-glutathione (MM-GSH). This results suggested that MM-CysGly, which is recognized as a major component of methylmercury in rat bile, can be easily reabsorbed from the intestine. These results indicate that not only MM-GSH and MM-Cys but also MM-CysGly may play important roles in the intestinal reabsorption of methylmercury during its enterohepatic circulation. When the ligated intestine was pretreated with probenecid and acivicin, the intestinal absorption of MM-GSH was depressed much more than in the case of treatment with acivicin alone. This indicates the possibility that there are at least two systems for intestinal transport of MM-GSH, i.e. gamma-glutamyltranspeptidase (GGT)-dependent and -independent systems.

Animals↗
PubMed1991

Approach to the analysis of diuretics and masking agents by high-performance liquid chromatography-mass spectrometry in doping control.

The application of thermospray and plasmaspray high-performance liquid chromatography-mass spectrometry to the analysis of diuretics and probenecid has been investigated. The latter method gave better ionization efficiency than the former, and its response was optimized by altering the solvent composition: best results were obtained with water-methanol-acetonitrile-trifluoroacetic acid. Using different proportions of these solvents, three isocratic systems were developed to separate the compounds under study. The principal characteristic of plasmaspray positive-ion mass spectra was a protonated molecular ion and very little fragmentation was evident. In the negative ionization mode, the plasmaspray method gave mass spectra showing more fragmentation, which resulted in additional structural information. The ability of trifluoroacetic acid to form negative cluster ions precluded its use as a mobile phase component. The minimum detectable amounts determined by the analysis in the positive-ion mode was compound-dependent, but generally ca. 10-150 ng. In many cases the compounds could be detected in urine extracts.

Chromatography, High Pressure Liquid↗
PubMed1992

High-performance liquid chromatographic determination of diuretics in urine by micellar liquid chromatography.

The use of micellar liquid chromatography for the determination of diuretics in urine by direct injection of the sample into the chromatographic system is discussed. The retention of the urine matrix at the beginning of the chromatograms was observed for different sodium dodecyl sulphate (SDS) mobile phases. The eluent strengths of a hybrid SDS-methanol micellar mobile phase for several diuretics were compared and related to the stationary phase/water partition coefficient with a purely micellar mobile phase. The urine band was appreciably narrower with a mobile phase of 0.05 M SDS-5% methanol (v/v) at 50 degrees C (pH 6.9). With this mobile phase the determination of bendroflumethiazide and chlorthalidone was adequate. Acetazolamide, ethacrynic acid, furosemide, hydrochlorothiazide and probenecid were overlapped by the urine matrix, and the retention of amiloride and triamterene was too long.

Acetazolamide↗
PubMed1987

Some organic acids attenuate the effects of furosemide on the endocochlear potential.

A series of organic acid transport inhibitors significantly reduced the endocochlear potential (EP) decline produced by furosemide in the chinchilla. Probenecid, sodium salicylate and penicillin G were much more effective than novobiocin, meclofenamate or diatrizoate. Inhibitors of organic base transport, choline and N-methyl nicotinamide, had no effect on the furosemide-induced drop of the EP. These findings suggest that at least part of furosemide ototoxicity may be mediated by organic acid transport.

Animals↗
PubMed1990

Organic acids do not alter the cochlear effects of ethacrynic acid.

Previous studies have shown a reduction of the ototoxicity of furosemide in chinchillas pretreated with organic acid transport inhibitors. The current studies were designed to investigate whether such a protective effect could be observed in chinchillas receiving ethacrynic acid. Chinchillas weighing 400-600 g were injected with saline followed by ethacrynic acid 12.5 mg/kg i.v. (controls) or one of three organic acids (probenecid, penicillin G and or sodium salicylate) 50 mg/kg i.v., thirty minutes prior to ethacrynic acid injection (experimentals). Endocochlear potential (EP) and compound action potential of the eighth nerve (CAP) elicited by click stimuli were simultaneously monitored before and after injection in both groups. The mean change in EP and CAP findings are consistent with observations by other investigators of the actions of these loop diuretics in the isolated loop of Henle. In the latter tissues, the 'furosemide-like loop diuretics' appear to have a different mechanism of action than does ethacrynic acid. It appears from the findings of the present study that the actions of furosemide and ethacrynic acid on the cochlea are by different mechanisms as well.

Action Potentials↗
PubMed1984

Distribution of 5-hydroxytryptamine and indolealkylamine metabolites in the American cockroach, Periplaneta americana L.

A procedure is described for simultaneous estimation of tryptophan (TP), 5-hydroxytryptophan (5-OHTP), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), N-acetyl 5-hydroxytryptamine (NA5-HT) and N-acetyldopamine (NADA) using high performance liquid chromatography with coulometric electrochemical detection. The procedure has been used to determine the distribution of these compounds in the central nervous system of the American cockroach, Periplaneta americana. The ratio of TP:5-HT is greatest in the cerebral ganglia (6.5) with lesser ratios evident in the thoracic ganglia (15.5-18.9) and abdominal ganglia (9.6-11.2). Relatively low concentrations of 5-OHTP and NA5-HT were observed in the cerebral ganglia whereas 5-HIAA was not detected. Incubation of ganglia resulted in increased concentrations of NA5-HT. Reserpine reduced levels of 5-HT and NADA whereas probenecid caused a marked reduction in TP and slight elevation of NADA levels. No MAO activity was detected in the central nervous system.

5-Hydroxytryptophan↗
PubMed1994

Is cyclic AMP involved in excitatory amino acid-evoked adenosine release from rat cortical slices?

Activation of both N-methyl-D-aspartate (NMDA) and non-NMDA receptors releases endogenous adenosine from superfused rat cortical slices. NMDA-evoked adenosine release is Ca(2+)-dependent and results from the extracellular degradation of a released nucleotide, whereas non-NMDA receptor activation releases adenosine per se in a Ca(2+)-independent manner. IBMX selectively inhibits NMDA- but not non-NMDA-evoked adenosine release. Forskolin, but not 1,9-dideoxy-forskolin, produced a slight but significant increase in NMDA-evoked adenosine release, suggesting that the formation of cyclic AMP may somehow be involved. The inhibition of NMDA-evoked adenosine release by IBMX is not accompanied by enhanced cyclic AMP recovery in superfusates, nor is release diminished when cyclic AMP transport is inhibited by probenecid, suggesting that the adenosine is not derived from the extracellular metabolism of released cyclic AMP. It is possible that 5'AMP, derived from the intracellular conversion of cyclic AMP by phosphodiesterase, might be released during NMDA receptor activation. However, more selective inhibitors of the specific phosphodiesterase isozymes known to be located in the cortex failed to diminish NMDA-evoked adenosine release. Therefore, the effects of both forskolin and IBMX on NMDA-evoked adenosine release could be nonspecific, coincidental and unrelated to their actions on cyclic AMP levels in the cortex. However, it is also possible that a novel IBMX-sensitive phosphodiesterase plays a primary role in converting cyclic AMP to 5'AMP intracellularly during NMDA receptor activation; the 5'AMP could then exit the cells and be converted to adenosine extracellularly.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Glucuronidation of 3'-azido-3'-deoxythymidine in human liver microsomes: enzyme inhibition by drugs and steroid hormones.

The molecular form of UDP-glucuronosyltransferase involved in the catalysis of 3'-azido-3'-deoxythymidine (AZT)-5'-O-glucuronide was characterized in human liver microsomes. The specific activity (1.3 nmol/min per mg protein) in transplantable liver was more than 2-times higher than in post-mortem fragments. Liver microsomes from patients suffering Crigler-Najjar syndrome, who are genetically deficient in bilirubin UDP-glucuronosyltransferase, could also glucuronidate AZT to a similar extent, thus indicating that this protein was not involved in that process. A genetically engineered V79 cell line stably expressing a cDNA which encodes a human isozyme active towards 1-naphthol was unable to glucuronidate AZT. Clinically used drugs, most of them being glucuronidated, were tested as potential inhibitors of the glucuronidation of AZT in human liver microsomes. The drugs chemically related to 2-phenylpropionic acid, naproxen and flurbiprofen, and the steroid compounds testosterone, estrone and ethynylestradiol strongly inhibited AZT glucuronidation. Codeine and morphine also decreased the reaction rate although to a lower extent. Except estrone which elicited a partial competitive inhibition, ethynylestradiol, flurbiprofen naproxen and testosterone could competitively inhibit AZT glucuronidation with an apparent Ki of 38, 50, 172 and 250 microM, respectively. The results suggest that these drugs were substrates of the same isozyme(s) involved in AZT glucuronidation. Probenecid was a weak inhibitor of the reaction (Ki 900 microM), only when non-disrupted microsomes were used. This drug may compete with the anion carrier system involved in the microsomal uptake of UDP-glucuronic acid.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Preparation and biological characteristics of 99mTc-diol a renal agent.

The present work concerns the production of 1,2-dihydroxypropyl-1-phosphonic acid (diol) by acid hydrolysis of (-cis) 1,2-epoxypropylphosphonic acid (phosphomycin), and its formulation as a kit easily labeled with [99mTc]pertechnetate. Biodistribution studies and whole-body autoradiographies in mice show that 99mTc-diol has a specific affinity for the kidneys: it is rapidly cleared from the blood and excreted in urine (12.09 +/- 6.40% ID are excreted in urine at 5 min and 70.81 +/- 2.41% ID at 30 min post-injection). Part of the injected activity remains in the kidney cortex sufficiently long to permit kidney imaging (5.66 +/- 0.91% ID is still in kidneys 1 h post-injection). In comparison with other agents which also localize in the kidney cortex, such as 99mTc-DMSA and 99mTc-glucoheptonate (99mTc-GHA), the main differences are the following: the peak of renal activity is reached early in the 5 min post-injection period for 99mTc-diol, only at about 10 min post-injection for 99mTc-GHA and after 3 h post-injection for 99mTc-DMSA. The uptake of 99mTc-diol by other organs, especially by bones, is much smaller than in the case of 99mTc-DMSA (1.25 +/- 0.11% ID of 99mTc-diol compared to 11.31 +/- 1.17% ID of 99mTc-DMSA, 1 h post-injection). Unlike 99mTc-DMSA, the biodistribution of 99mTc-diol is not significantly influenced by acid-base imbalance, in addition, its renal uptake decreases in the presence of probenecid whereas its urinary excretion increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Imbalance↗
PubMed2005

Functional expression of pig renal organic anion transporter 3 (pOAT3).

With the cloning of pig renal organic anion transporter 1 (pOAT1) (Biochimie 84 (2002) 1219) we set up a model system for comparative studies of cloned and natively isolated membrane located transport proteins. Meanwhile, another transport protein involved in p-aminohippurate (PAH) uptake on the basolateral side of the proximal tubule cells was identified, designated organic anion transporter 3 (OAT3). To explore the contribution of pOAT1 to the PAH clearance in comparison to OAT3, it was the aim of this study to extend our model by cloning of the pig ortholog of OAT3. Sequence comparisons of human organic anion transporter 3 (hOAT3) with the expressed sequence tag (EST) database revealed a clone and partial sequence of the pig renal organic anion transporter 3 (pOAT3) ortholog. Sequencing of the entire open reading frame resulted in a protein of 543 amino acid residues encoded by 1632 base pairs (EMBL Acc. No. AJ587003). It showed high homologies of 81%, 80%, 76%, and 77% to the human, rabbit, rat, and mouse OAT3, respectively. A functional characterization of pOAT3 in Xenopus laevis oocytes yielded an apparent Km (Kt) for [3H]estrone sulfate of 7.8 +/- 1.3 microM. Moreover, pOAT3 mediated [3H]estrone sulfate uptake was almost abolished by 0.5 mM of glutarate, dehydroepiandosterone sulfate, or probenecid consistent with the hallmarks of OAT3 function.

Amino Acid Sequence↗
PubMed2006

Schisandrin B: a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1.

We recently reported that schisandrin B (Sch B) was a novel P-glycoprotein (P-gp) inhibitor. In this study, we revealed that Sch B was also an effective inhibitor of multidrug resistance-associated protein 1 (MRP1). The activities of Sch B to reverse MRP1-mediated drug resistance was tested using HL60/ADR and HL60/MRP, the human promyelocytic leukemia cell lines with the overexpression of MRP1 but not P-gp. Sch B resumed daunorubicin and carboxyfluorescein diacetate (CFDA, a specific substrate for MRP1) accumulation and retention in HL60/ADR cells in a time and concentration dependent manner. At the equimolar concentration, Sch B demonstrated significantly stronger potency than probenecid, a MRP1 inhibitor. This study, together with the previous findings, demonstrated that Sch B was a dual inhibitor of P-gp and MRP1, a type suggested to be preferable to the use of combination of two specific modulators to prevent drug-drug interaction and cumulative toxicities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗