Phenolphthalein-induced fixed drug eruption: a cutaneous complication of laxative use in a child.
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Cathartics↗
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A Note on the Relative Sensitivity of the Benzidine and Phenolphthalein Tests for Blood.
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Journal Article↗
The phenolphthalein follies: purgation and the pleasure principle in the early twentieth century.
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Digestive System Diseases↗
The effect of alcohols on the hydrolysis of sodium phenolphthalein diphosphate by prostatic extracts.
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Journal Article↗
Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion.
BACKGROUND/AIMS: The treatment of hyperkalemia in patients with renal insufficiency often includes the ingestion of sorbitol and a cation exchange resin. Sorbitol alone may be used to remove sodium and water from overloaded patients. The efficacy of these regimens has never been compared with other laxative or laxative-resin combinations. The aim of the study was to compare the relative effect of three laxatives with different mechanisms of action, alone and in combination with resin, on fecal sodium and potassium excretion. METHODS: Sodium, potassium, and water excretion in 12-hour stool collections were analyzed after various laxative-resin combinations in normal subjects. RESULTS: Correctol (yellow phenolphthalein) (Schering Plough Health Care Products, Memphis, TN) was more effective than sorbitol or sodium sulfate in causing fecal sodium and potassium loss. Resin recovery in stool was much greater with phenolphthalein than with other laxatives, and more potassium was excreted in stool with phenolphthalein-resin than with phenolphthalein alone or other laxative-resin combinations. Sorbitol caused more undesirable gastrointestinal symptoms than did sodium sulfate or phenolphthalein. CONCLUSIONS: In normal people, phenolphthalein (1) is preferable to other laxatives in causing fecal sodium and potassium excretion, (2) hastens resin transit through the intestine compared with other laxatives, and (3) produces greater fecal potassium excretion when combined with resin than phenolphthalein alone or other laxative-resin combinations.
Cathartics↗
Regulation of 86Rb+ ion transport across polarized human colonocytes by bis-phenolic compounds.
1. Phenolphthalein, a well-known laxative, stimulates the secretion of Na+ and Cl- ions and accompanying water into the intestinal tract. Measurement of 86Rb+ efflux from several, but not all, cell types indicates that phenolphthalein also results in release of cellular K+ ions. 2. In the present study, the transport of 86Rb+ across human colonocyte cells (T84) cultured on trans-well inserts was examined. The T84 cells were cultured until they developed tight junctions and a high trans-epithelial resistance. 3. Results show that phenolphthalein applied to the apical, but not the basolateral, surface of cells causes the release of 86Rb+ from the apical surface. Basolateral treatment of cells with phenolphthalein had no effect on the release of 86Rb+. 4. Simultaneously with the increased 86Rb+ efflux, indirect evidence of enhanced Na+/K+-ATPase activity was also observed. 5. Although ouabain inhibited the increased Na+ pump activity, it did not affect apical 86Rb+ release. 6. As evidenced by near steady state 86Rb+ uptake data, the increased Na+/K+-ATPase activity was insufficient to restore intracellular concentrations of K+ in the presence of phenolphthalein. 7. 4,4(9-Fluorenylidene)diphenol, a homologue of phenolphthalein, had a similar effect on 86Rb+ transport by T84 cells. 8. These results indicate a primary stimulation of 86Rb+ efflux from the apical surface of polarized T84 cells by apically applied bis-phenolic compounds. 9. A secondary stimulation of the basolateral Na+/K+-ATPase is thought to result from intracellular Na+ increase, as documented in several other cell types exposed to bis-phenolic compounds, although not directly measured in these experiments. 10. The results also indicate that bis-phenolic compounds interact specifically with some apical but not basolateral membrane structures in regulating 86Rb+ efflux from polarized T84 cells.
Biological Transport↗
Expression and significance of nerve growth factor receptor p75 in rats' cathartic colonic wall.
OBJECTIVE: To investigate the expression of nerve growth factor receptor p75 in a normal and cathartic colon and its significance in the formation of the cathartic colon in rats. METHODS: Sixty Sprague-Dawley rats were equally divided into normal control group, rhubarb group and phenolphthalein group. A model of the cathartic colon was constructed by gastric infusion with rhubarb or phenolphthalein in rats. The first dose of rhubarb and phenolphthalein was both 200 mg/kg/d and was increased by 200 mg/kg/d with each passing day. The last dose of rhubarb and phenolphthalein was 3200 mg/kg/d and 4200 mg/kg/d, respectively. The transit function of colon was measured by the Chinese ink expulsion test; the p75 in colon wall was determined by the immunohistochemical method. RESULTS: The transit speed was much slower in the cathartic colon group than that in the control group. The imprinted Chinese ink length and the ratio of imprinted length/total colon length in the rhubarb-induced cathartic colon was significantly shorter than that of the control group (77.38 +/- 8.42 vs 94.25 +/- 7.07 cm, P < 0.01). Those in the phenolphthalein-induced group (83.38 +/- 9.75 cm) were also significantly shorter than those of the control group but to a lesser degree (P < 0.05). p75 was abundantly expressed in the submucosal nerve plexus and weakly expressed in the myenteric plexus. The expression of p75 was much higher in the rhubarb-induced group. The expression was strongly positive in the submucosal nerve plexus, significantly higher than that in the controls (P < 0.01). In the myenteric plexus, p75 was also highly expressed (P < 0.05). In the case of the phenolphthalein-induced group, the expression of p75 was positive in the submucosal nerve plexus but was positive in the myenteric plexus of three rats only. The remaining rats were negative or weakly positive. This was not significantly different from that of the control group. CONCLUSIONS: The abnormal expression of p75 in cathartic colon probably has some effect on the degeneration or apoptosis of neuronal cells in the enteric nerve plexus, with a subsequent pathological change of the enteric nervous system, and thus leads to abnormalities in colonic dynamics. The kind of lesion is probably associated with long-term use of irritative cathartics.
Animals↗
Uptake of glucuronides into isolated hepatocytes and their effects on glucuronide and sulphate conjugation.
Uptake studies, using radioactive labelled glucuronides, have demonstrated the ability of 4-nitrophenyl glucuronide and phenolphthalein glucuronide to enter isolated rat hepatocytes. Of these glucuronides 4-nitrophenyl glucuronide was distributed in a similar manner to O-methylglucose, whereas phenolphthalein glucuronide was bound to cellular constituents. Phenolphthalein glucuronide had an effect on theconjugation of harmol in the isolated hepatocytes when glucuronidation was found to be markedly inhibited and sulphation slightly stimulated. The glucuronidation of 4-nitrophenol, 4-methylumbelliferone and harmol in native microsomes was inhibited by phenolphthalein glucuronide. 4-Nitrophenyl glucuronide and also naphthyl glucuronide were without effect both in hepatocytes and microsomes. In control hepatocytes harmine was metabolized to form harmolsulphate mainly. Phenolphthalein glucuronide only affected this metabolic pattern to a minor extent. However, in hepatocytes from phenobarbital treated rats, where the rate of harmine metabolism is increased about five times and the main metabolite is harmol glucuronide, phenolphthalein glucuronide inhibited the formation of the conjugate with a concomitant increase in free harmol.
Animals↗
Evidence for multiple glucuronide transporters in rat liver microsomes.
The transport of glucuronides across the endoplasmic reticulum membrane is an important step in the overall process of biotransformation, although the mechanism remains unclear and the participating transporters are unidentified. Using a rapid filtration assay in combination with liquid chromatography-mass spectrometry, we measured the transport of a variety of beta-D-glucuronides in rat liver microsomes and investigated the substrate specificity of the participating transporter(s) by inhibition studies. Time-dependent and bi-directional transport of phenolphthalein glucuronide was detected and the kinetic parameters for transport were determined. The K(m) and V(max) values of high affinity transport were 26microM and 3.9nmol/min/mg protein, respectively. Phenolphthalein glucuronide transport was inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and N-ethylmaleimide. Transport inhibition studies revealed competition between three glucuronides: phenolphthalein glucuronide, estradiol 17-glucuronide and naphthol AS-BI glucuronide indicating that they share a common transporter in the endoplasmic reticulum membrane. Their transport was inhibited by phenolphthalein, but was not affected by p-nitrophenyl glucuronide, naphthyl glucuronide or d-glucuronate. Morphine 3-glucuronide transport was not inhibited by any of the latter four compounds or by phenolphthalein glucuronide. This novel experimental approach has produced data consistent with the presence of multiple (at least three) transporters catalyzing the transport of glucuronides through the endoplasmic reticulum membrane. These data also indicate that the size and/or shape of the aglycone rather than the glucuronic acid moiety per se is an important determinant of transporter specificity.
Animals↗
The heterogeneity of uridine diphosphate glucuronyltransferase from rat liver.
1. The glucuronide conjugation of p-nitrophenol, phenolphthalein, o-aminophenol and 4-methylumbelliferone by rat liver microsomes has been studied. The detergent Triton X-100 activated UDP-glucuronyltransferase activity towards all these substrates, therefore the optimum activating concentration was added in all experiments. 2. Mg(2+) enhanced the conjugation of the substrates. 3. With phenolphthalein substrate inhibition occurred but this could be relieved by adding albumin, which binds excess of phenolphthalein. 4. Kinetic constants of the substrates and UDP-glucuronate have been determined. Mutual inhibition was found with the substrates p-nitrophenol, 4-methylumbelliferone and phenolphthalein. p-Nitrophenol conjugation was inhibited competitively by phenolphthalein and 4-methylumbelliferone. 5. o-Aminophenol did not inhibit the conjugation of the other three substrates because these are conjugated preferentially to o-aminophenol. 6. It is concluded that the four substrates are conjugated by one enzyme at the same active site.
Albumins↗
Antagonism of ATP responses at P2X receptor subtypes by the pH indicator dye, Phenol red.
1 Many types of culture media contain a pH-sensitive dye. One commonly occurring dye, Phenol red sodium (Na(+)) salt, was tested for blocking activity at rat P2X(1-4) receptors (P2X(1-4)Rs) expressed in Xenopus oocytes. 2 Phenol red Na(+)-salt antagonised adenosine 5'-triphosphate (ATP) responses at P2X(1)R (IC(50), 3 microM) and, at higher concentrations, also blocked P2X(2)R and P2X(3)R. Phenol red Na(+)-salt, purified of lipophilic contaminants, blocked P2X(1)R and P2X(3)R by acting as an insurmountable antagonist. 3 Two lipophilic extracts of Phenol red antagonised ATP responses at P2XRs. Extract A was a potent antagonist at P2X(1)R (IC(50), 1.4 microM), whereas extract B was a potent antagonist at P2X(3)R (IC(50), 4.1 microM). A bisphenolic compound (RS151030) found in these extracts was a potent antagonist at P2X(1)R (IC(50), 0.3 microM) and at P2X(3)R (IC(50), 2.4 microM). 4 Phenolphthalein base was a potent irreversible antagonist at P2X(1)R (IC(50), 1 microM), whereas Phenolphthalein K(+)-salt was 25-fold less potent here. 5 Phenolphthalein base was a reversible antagonist of ATP responses at rat P2X(4)R (IC(50), 26 microM), whereas Phenolphthalein K(+)-salt was inactive. 6 Dimethyl sulphoxide (DMSO), used to dissolve lipophilic extracts, showed pharmacological activity by itself at rat P2X(1)R and P2X(4)R. 7 Thus, Phenol red and related compounds are antagonists at rat P2X(1)R, but are also active at other rat P2XRs. Phenolphthalein base is a newly identified, low potency antagonist of ATP responses at P2X(4)R. Culture media containing these red dyes should be used cautiously in future pharmacological studies of P2XRs. Also, wherever possible, the solvent DMSO should be used with caution.
Adenosine Triphosphate↗
High-affinity rat anti-fluorescein monoclonal antibody with unique fine specificity properties including differential recognition of dynamic ligand analogues.
The ability of antibodies to specifically select and stabilize through binding one or more isomers of highly dynamic ligands remains a relatively unexplored immunochemical problem. The experimental strategy employed in this study was to elicit homogeneous antibodies to polyaromatic fluorescein which exists in one isomeric form. The binding properties of a monoclonal rat antifluorescein antibody specific to a given isomer were quantitatively studied to determine the capacity to bind dynamic analogues of fluorescein which exists in multiple isomers. To generate monoclonal anti-fluorescein antibodies that reacted with specific dynamic analogues of fluorescein possessing unconjugated aromatic ring systems, immune spleenocytes from Lou/M rats immunized with FITC(I)-KLH were fused with Balb/c SP2/0-Ag14 murine myeloma cells forming rat-mouse hybridomas. Cell line P2A12-1-C8 was selected for further characterization from the original 23 stable rat hybrids, since it produced a monoclonal antibody with a binding affinity 2.0 x 10(10)/M for fluorescein based on dissociation rate measurements. P2A12-1-C8 exhibited significant reactivity with HPF and phenol red, which are dynamic structural analogues of the homologous fluorescein ligand. No reactivity was demonstrated with phenolphthalein, which based on relative chemical structures was expected to be more reactive than phenol red. Computer-based molecular modeling and energy minimization studies of fluorescein, HPF, phenol red, and phenolphthalein showed that in terms of the most energetically favorable orientation of the three aromatic rings, phenol red more closely simulated fluorescein than phenolphthalein. The results were analyzed in terms of the mechanisms of dynamic ligand stabilization and binding involving accommodation of specific ligand isomers by energetically permissible conformational states exhibited by an antibody active site. Thus, antibody reactivity of an anti-fluorescein antibody with phenol red and phenolphthalein was dictated more by ligand dynamics and aromatic orientation than by chemical structure similarities.
Absorption↗
Conjugation of organic compounds in isolated hepatocytes from a marine fish, the plaice, Pleuronectes platessa.
A method is described for the preparation of viable hepatocytes from a marine fish, the plaice. Their ability to detoxify organic compounds was measured by the formation of glucuronic acid and sulphate conjugates with the model substrates 1-naphthol and phenolphthalein. 1-Naphthol was conjugated three- to four-fold faster than phenolphthalein and glucuronidation predominated with both substrates. Strong substrate inhibition of glucuronidation was observed with 200 microM 1-naphthol or phenolphthalein. No measurable sulphate conjugation was detected with phenolphthalein. Treatment of fish with 3-methylcholanthrene induced formation of both glucuronide and sulphate conjugates by two- to three-fold. Compared with rat hepatocytes, the extent of sulphation was 100-fold lower in plaice hepatocytes whereas glucuronide formation was only 10-fold lower. The observations indicate that isolated plaice hepatocytes provide a suitable system for studies of the detoxication of xenobiotic pollutants in fish liver.
Animals↗
Biliary excretion of sulfated bile acids and organic anions in zone 1- and zone 3-injured rats.
BACKGROUND AND AIMS: There are several reports on the biliary excretion of bile acids and organic anions in zone 1- and zone 3-injured rat liver, but the results are controversial. In order to dissolve the discrepancy between previous works about the role of hepatic zonation on the hepatic handling of the substrates of multidrug resistance protein 2, the biliary excretion of sulfated bile acids, pravastatin and phenolphthalein glucuronide was studied in zone 1- and zone 3-injured rats. METHODS: Zone 1 and zone 3 injury were caused by allyl alcohol and bromobenzene, respectively. Bile acid sulfates, pravastatin and phenolphthalein glucuronide were administered i.v. to bile duct-cannulated rats, and their biliary excretion was studied. RESULTS: The biliary excretion of a tracer dose of taurolithocholate-3-sulfate and its excretory maximum were unchanged in zone 1 injury, but were diminished in zone 3 injury, whereas the biliary excretion of taurochenodeoxycholate-3-sulfate was unchanged in zone 1 and zone 3 injury. The biliary excretion of pravastatin and phenolphthalein glucuronide was markedly decreased only in zone 3 injury, whereas the excretory maximum of phenolphthalein glucuronide was decreased in both zone 1 and zone 3 injury. CONCLUSIONS: These findings indicate that zone 3 is important for the biliary excretion of substrates of multidrug resistance protein 2.
ATP-Binding Cassette Transporters↗
Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs.
Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.
Animals↗
Effect of butylated hydroxyanisole on hepatic glucuronidation and biliary excretion of drugs in mice.
Inhibition of glucuronidation by depletion of UDP-glucuronic acid from liver impairs the hepatobiliary transport of glucuronidated xenobiotics. However, it is not known if enhancement of hepatic glucuronidation increases the biliary excretion of these compounds. Therefore, the effect of treatment with butylated hydroxyanisole (BHA), which increases hepatic glucuronidation capacity, on the biliary excretion of compounds undergoing glucuronidation was studied in mice. BHA-feeding (1% for 10 days) increased hepatic UDP-glucuronic acid content by 240% and enhanced hepatic UDP-glucuronosyltransferase activities (expressed per kg body weight) toward valproic acid, phenolphthalein, iopanoic acid and bilirubin 220, 180, 120 and 60%, respectively. BHA treatment did not influence the biliary excretion of unmetabolized cholephils, phenol-3,6-dibromphthalein disulphonate and phenolphthalein glucuronide, but enhanced that of phenolphthalein (+108%), iopanoic acid (+63%) and bilirubin (+33%) as glucuronides. However, these increases were apparent only in the initial phase of excretion. In contrast, BHA markedly decreased (-43%) the biliary excretion of valproic acid glucuronides. Simultaneously, BHA increased the urinary excretion of the glucuronides of phenolphthalein (+48%), iopanoic acid (+450%) and valproic acid (+150%). A shift in the distribution of iopanoic acid and valproic acid and metabolites from liver to kidney was also apparent in BHA-fed mice. Thus, enhanced glucuronidation does not facilitate the biliary excretion of all glucuronidated compounds and only transiently increases others. It is likely that this phenomenon is the result of the glucuronides readily entering the plasma and being excreted by the kidney.
Animals↗
Quinine sensitive changes in cellular Na+ and K+ homeostasis of COS-7 cells caused by a lipophilic phenol red impurity.
An impurity of phenol red (PRI) has been shown to markedly alter the intracellular Na+ and K+ homeostasis of several cell types. The effect of PRI seems to involve intracellular Ca(++)-dependent mechanisms. Using COS-7 cells as a model, we further characterized the mechanism of action of PRI by measuring cellular Na+/K+ contents and 86Rb+ efflux. Similar to human skin fibroblasts, in COS-7 cells calmodulin inhibition moderated the cationic transport effects of PRI. A TMB-8 dependent intracellular Ca++ pool does not seem to be involved in these transport events. We found no evidence for participation of the transcriptional-translational machinery in the effect of PRI. Both quinine and quinidine are able to prevent nearly all changes caused by PRI in the cellular Na+/K+ contents and 86Rb+ efflux. Although phenol red contained multiple impurities by high performance liquid chromatography (HPLC), phenolphthalein, a structurally close relative of phenol red, was free of any detectable contamination. Phenolphthalein elicited qualitatively similar transport changes to those observed during exposure to PRI. Regardless of the exact mechanism of action, we propose that the as yet unidentified substance is not a cellular toxin, rather it is a cationic transport modulator. Directly or indirectly, it may interact with the cellular Ca++/calmodulin system and activate some quinine/quinidine sensitive transport processes. This transport process is likely to be a Ca(++)-sensitive K+ channel but, due to the lack of specificity of quinine and quinidine, other transport mechanisms must be also considered. The chemical nature of PRI may be similar to phenolphthalein.
Animals↗