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PubMed1990

Effects of indole-pyruvic acid on sleep and food intake in the rat.

Indole-pyruvic acid was studied for its short- and long-term effects on electroencephalographic sleep and on food intake in rats implanted with cortical and muscular electrodes. Following a single injection, indole-pyruvic acid (10-50 mg kg-1 i.p.) reduced by 16-23 min (range) the latency of the first slow-wave episode in a dose-related fashion and produced a significant increase in slow-wave sleep time (12-40%) in doses of 10-30 mg kg-1. Rapid eye movement sleep latency and rapid eye movement sleep time were increased (by 23-37 min) and reduced (57-71%) respectively. The effects of indole-pyruvic acid on slow-wave sleep time were still present after 3, 7 and 14 days of chronic administration (10 mg kg-1 day-1), whereas tolerance to the effect of indole-pyruvic acid on rapid eye movement sleep was observed. Daily food consumption was reduced (20-28%) by acute administration of indole-pyruvic acid (15-30 mg kg-1 i.p.), but tolerance developed after 5 days of repeated injections. These findings are in accordance with previous evidence suggesting that indole-pyruvic acid effects may be related to the activation of central serotonin neurons, which are involved in the inhibitory control of sleep and food intake.

Animals↗
PubMed2003

Substituent effect on the reductive N-dearylation of 3-(indol-1-yl)-1,2-benzisoxazoles by rat liver microsomes.

The reductive metabolism of a series of 3-(indol-1-yl)-1,2-benzisoxazoles was examined in vitro using rat liver microsomes. 3-(Indol-1-yl)-1,2-benzisoxazole was reduced to the corresponding amidine (resulting from N-O bond cleavage) under anaerobic conditions. The reaction required viable microsomes and NADPH and was inhibited by carbon monoxide, air, and ketoconazole, suggesting the involvement of cytochrome p450 enzymes. The amidine was subsequently nonenzymatically hydrolyzed to 1-salicylindole, which in turn was hydrolyzed to indole. Addition of electron-withdrawing substituents (Cl-, MeSO2-) at the 6-position of the benzisoxazole ring resulted in a significant increase in the rate of substrate reduction. Introduction of electron-withdrawing substituents on the indole ring likewise increased the rate of substrate consumption but caused a substituent-dependent shift of the site of bond cleavage from the 1,2-isoxazole N-O bond to the C-N bond linking the 1,2-benzisoxazole to the indole moiety. In the case of 3-(2-chloro-3-methanesulfoxylindol-1-yl)-1,2-benzisoxazole, C-N bond cleavage was nearly quantitative, and products resulting from N-O bond reduction were not observed. The overall rates of 3-(indol-1-yl)-1,2-benzisoxazoles reduction were found to be substrate concentration-dependent and observed Michaelis-Menten-type behavior. The apparent Vmax of substrate reduction by rat liver microsomes correlated negatively with the free energy of the lowest unoccupied molecular orbitals (ELUMO) calculated semiempirically using a parameterized model 3 (PM3), and suggested that the initial electron transfer was rate-determining and that the ELUMO could be used as an indication of the susceptibility of 1,2-isoxazoles to undergo reductive metabolism.

Air↗
PubMed1994

Biodegradable, effective substitute for xylene in the Ehrlich indole procedure.

Three extracting reagents were compared for effectiveness in the Ehrlich indole procedure: xylene (the recommended reagent), Hemo-De (a terpene-based product containing d-limonene), and Micro-Clear (an isoparaffinic hydrocarbon). Thirty-three strains representing 12 species of indole-positive aerobes or facultative anaerobes and 50 strains representing 11 species of indole-positive strict anaerobes were tested using the three reagents. Xylene extraction allowed indole detection in all of the isolates tested. Micro-Clear allowed detection in all of the aerobic isolates and in 49 of 50 anaerobes. Hemo-De allowed indole detection in 32 of 33 aerobes and in 49 of 50 anaerobes. There was no significant difference in the results among the reagents. Because Micro-Clear is biodegradable, nonflammable, noncarcinogenic, and odorless, we feel that this product should be considered a safe and effective substitute for xylene in the Ehrlich indole procedure.

Bacterial Typing Techniques↗
PubMed2004

Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice.

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are promising cancer chemopreventive agents in rodent models, but there is a paucity of data on their pharmacokinetics and tissue disposition. The disposition of I3C and its acid condensation products, DIM, [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr(1)), indolo[3,2b]carbazole (ICZ) and 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM) was studied, after oral administration of I3C (250 mg/kg) to female CD-1 mice. Blood, liver, kidney, lung, heart, and brain were collected between 0.25 and 24 h after administration and the plasma and tissue concentrations of I3C and its derivatives determined by high-performance liquid chromotography. I3C was rapidly absorbed, distributed, and eliminated from plasma and tissues, falling below the limit of detection by 1 h. Highest concentrations of I3C were detected in the liver where levels were approximately 6-fold higher than those in the plasma. Levels of DIM, LTr(1), and HI-IM were much lower, although they persisted in plasma and tissues for considerably longer. DIM and HI-IM were still present in the liver 24 h after I3C administration. Tissue levels of DIM and LTr(1) were found to be in equilibrium with plasma at almost every time point measured. In addition to acid condensation products of I3C, a major oxidative metabolite (indole-3-carboxylic acid) and a minor oxidative metabolite (indole-3-carboxaldehyde) were detected in plasma of mice after oral administration of I3C. ICZ was also tentatively identified in the liver of these mice. This study shows for the first time that, after oral administration to mice, I3C, in addition to its acid condensation products, is absorbed from the gut and distributed systemically into a number of well-perfused tissues, thus allowing the possibility for some pharmacological activity of the parent compound in vivo.

Administration, Oral↗
PubMed1994

Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.

In uremia there is a marked elevation of serum levels of indoxyl sulfate due to its decreased renal clearance. Indoxyl sulfate is synthesized in the liver from indole which is produced by bacteria in the intestines. To determine the role of indoxyl sulfate in the progression of chronic renal failure, we administered indole, the precursor of indoxyl sulfate, to subtotally nephrectomized uremic rats. The oral administration of indole increased the serum levels of creatinine and blood urea nitrogen and decreased creatinine, inulin, and p-aminohippuric acid clearances. The glomerular sclerosis index in the indole-treated rats was higher than in the control uremic rats. After oral administration, indole could not be detected in the urine, but large amounts of its metabolite, indoxyl sulfate. Thus, indole administration stimulated glomerular sclerosis in a uremic model through the production of indoxyl sulfate.

Animals↗
PubMed2005

Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells.

Indole-3-carbinol, found in Brassica species vegetables (such as cabbage, cauliflower, and brussels spouts), exhibits antitumor effects through poorly defined mechanisms. Because several genes that regulate apoptosis, proliferation, and metastasis are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that indole-3-carbinol must mediate its activity through NF-kappaB modulation. We demonstrated that indole-3-carbinol suppressed constitutive NF-kappaB activation and activation induced by tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), and cigarette smoke; the suppression was not cell type specific, because activation was inhibited in myeloid, leukemia, and epithelial cells. This activation correlated with the sequential suppression of the IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, p65 acetylation, and NF-kappaB-dependent reporter gene expression. The NF-kappaB-regulated gene products cyclin D1, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), survivin, inhibitor-of-apoptosis protein-1 (IAP1), IAP2, X chromosome-linked IAP (XIAP), Bcl-2, Bfl-1/A1, TNF receptor-associated factor-1 (TRAF1), and Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) were all down-regulated by indole-3-carbinol. This down-regulation led to the potentiation of apoptosis induced by cytokines and chemotherapeutic agents. Indole-3-carbinol suppressed constitutive NF-kappaB activation in mononuclear cells derived from bone marrow of acute myelogenous leukemia patients, and this correlated with inhibition of cell growth. Overall, our results indicated that indole-3-carbinol inhibits NF-kappaB and NF-kappaB-regulated gene expression and that this mechanism may provide the molecular basis for its ability to suppress tumorigenesis.

Antineoplastic Agents↗
PubMed2003

Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs.

A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoquinone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases I and II activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-methyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC50<20.0 microg/ml in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethylphenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC50=0.4 microg/ml)) compared to colon (IC50>20.0 microg/ml) and stomach (IC50>20.0 microg/ml) cancer cells. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities were used. In a topoisomerase I-mediated relaxation assay using human placenta DNA topoisomerase I and supercoiled pHOTI plasmid DNA, 2-amino-3-ethoxycarbonyl-N-(4-fluorophenyl)-benz[f]indole-4,9-dione had the most potent inhibitory activity among the compounds tested. However, most of the compounds showed only weak inhibition of the DNA topoisomerase II-mediated KDNA (Kinetoplast DNA) decatenation assay, except for 2-amino-3-ethoxycarbonyl-N-(4-methylphenyl)-benz[f]indole-4,9-dione and 2-amino-3-ethoxycarbonyl-N-(2-bromoehtyl)-benz[f]indole-4,9-dione with a moderate inhibitory activity. These results suggest that several active compounds had relatively selective inhibitory activity against toposiomearse I compared to toposiomerase II. No obvious correlation was observed between the cytotoxicity of the individual compound and the inhibitory activity of DNA relaxation and decatenation by topoisomerase I and II, respectively, in vitro.

Antineoplastic Agents↗
PubMed2005

Indole hydroxylation by bacterial cytochrome P450 BM-3 and modulation of activity by cumene hydroperoxide.

Cytochrome P450 BM-3 from Bacillus megaterium catalyzed NADPH-supported indole hydroxylation under alkaline conditions with homotropic cooperativity toward indole. The activity was also found with the support of H2O2, tert-butyl hydroperoxide (tBuOOH), or cumene hydroperoxide (CuOOH). Enhanced activity and heterotropic cooperativity were observed in CuOOH-supported hydroxylation, and both the Hill coefficient and substrate concentration required for half-maximal activity in the CuOOH-supported reaction were much lower than those in the H2O2-, tBuOOH-, or NADPH-supported reactions. CuOOH greatly enhanced NADPH consumption and indole hydroxylation in the NADPH-supported reaction. However, when CuOOH was replaced by tBuOOH or H2O2, heterotropic cooperativity was not observed. Spectral studies also confirmed that CuOOH stimulated indole binding to P450 BM-3. Interestingly, a mutant enzyme with enhanced indole-hydroxylation activity, F87V (Phe87 was replaced by Val), lost homotropic cooperativity towards indole and heterotropic cooperativity towards CuOOH, indicating that the active-site structure affects the cooperativities.

Allosteric Regulation↗
PubMed2006

Indole localization in lipid membranes revealed by molecular simulation.

It is commonly known that the amino acid residue tryptophan and its side-chain analogs, e.g., indole, are strongly attracted to the interfacial region of lipid bilayers. Phenylalanine and its side-chain analogs, e.g., benzene, do not localize in the interface but are distributed throughout the lipid bilayer. We use molecular dynamics to investigate the details of indole and benzene localization and orientation within a POPC bilayer and the factors that lead to their different properties. We identify three sites in the bilayer at which indole is localized: 1), a site in the interface near the glycerol moiety; 2), a weakly bound site in the interface near the choline moiety; and 3), a weakly bound site in the center of the bilayer's hydrocarbon core. Benzene is localized in the same three positions, but the most stable position is the hydrocarbon core followed by the site near the glycerol moiety. Transfer of indole from water to the hydrocarbon core shows a classic hydrophobic effect. In contrast, interfacial binding is strongly enthalpy driven. We use several different sets of partial charges to investigate the factors that contribute to indole's and benzene's orientational and spatial distribution. Our simulations show that a number of electrostatic interactions appear to contribute to localization, including hydrogen bonding to the lipid carbonyl groups, cation-pi interactions, interactions between the indole dipole and the lipid bilayer's strong interfacial electric field, and nonspecific electrostatic stabilization due to a mismatch in the variation of the nonpolar forces and local dielectric with position in the bilayer.

Benzene↗
PubMed2003

Interaction of singlet molecular oxygen with melatonin and related indoles.

Singlet molecular oxygen (1O2) is one of the major agents responsible for (photo)oxidative damage in biological systems including human skin and eyes. It has been reported that the neural hormone melatonin (MLT) can abrogate 1O2-mediated cytotoxicity through its purported high antioxidant activity. We studied the interaction of MLT with 1O2 in deuterium oxide (D2O), acetonitrile and methanol by measuring the phosphorescence lifetime of 1O2 in the presence of MLT and related indoles for comparison. Rose bengal (RB) was used as the main 1O2 photosensitizer. The rate constant (kq) for the total (physical and chemical) quenching of 1O2 by MLT was determined to be 4.0 x 10(7) M(-1) s(-1) in D2O (pD 7), 6.0 x 10(7) M(-1) s(-1) in acetonitrile, and 6.1 x 10(7) M(-1) s(-1) in methanol-d1. The related indoles, tryptophan, 5-hydroxyindole, 5-methoxytryptamine, 5-hydroxytryptamine (5-OH-T, serotonin), 6-hydroxymelatonin (6-OH-MLT) and 6-chloromelatonin quenched 1O2 phosphorescence with similar kq values. We also compared the photosensitized photobleaching rate of MLT with that of other indoles, which revealed that MLT is the most sensitive to 1O2 bleaching. Hydroxylation of the indole moiety in 5-OH-T and 6-OH-MLT makes them more sensitive to photodegradation. In the absence of exogenous photosensitizers MLT itself can generate 1O2 with low quantum yield (0.1 in CH3CN) upon UV excitation. Thus, the processes we investigated may occur in the skin and eyes during physiological circadian rhythm (photo)signaling involving MLT and other indoles. Our results indicate that all the indoles studied, including MLT, are quite efficient yet very similar 1O2 quenchers. This directly shows that the exceptional antioxidant ability proposed for MLT is unsubstantiated when merely chemical mechanism(s) are considered in vivo, and it must predominantly involve humoral regulation that mobilizes other antioxidant defenses in living organisms.

Indoles↗
PubMed2000

[Indole derivatives in vegetables of the family Cruciferae].

The chemical background of the biological activities of vegetables of the Cruciferae family is considered. These vegetables contain alkaloids of the glucobrassicin group that are decomposed by the enzyme myrosinase (thioglucosidase, EC 3.2.3.1) released upon damage to the plant cells. This results in several indole derivatives, with ascorbigen and indole-3-carbinol predominating. In the gastrointestinal tract, these compounds form 5H,11H-indolo[3,2-b]carbazole, natural ligand of the aromatic hydrocarbon receptor (Ah receptor) and a functional analogue of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a dangerous xenobiotic. The indolocarbazole-Ah receptor complex activates the gene of CYP1A1, an isoenzyme of cytochrome P450-dependent monoamine oxidase, which enhances the 2-hydroxylation (inactivation) of estrogens. In its turn, the resulting lowered level of estrogens inhibits the growth of hormone-dependent tumors or prevents their appearance. The mechanism of xenobiotic inactivation, underlying the anticarcinogenic action of food products including vegetables of Cruciferae family and some homogeneous indole compounds, is similar. Some other effects of nutrient indole compounds, e.g., the inhibition of expression of the cyclin-dependent kinase 6 (CDK6) by indole-3-carbinol that leads to the cell cycle arrest in G1 phase, are also considered. Analysis of the biological effects of the Cruciferae diet has helped start clinical studies of indole-3-carbinol as an antitumor and anticarcinogenic remedy for patients with a high risk of tumor diseases.

Brassicaceae↗
PubMed1977

A study of antidepressant activity of some indole alkylamines.

The antidepressant characteristics of three indole alkylamines were investigated and compared with phenelzine and imipramine by utilising specific pharmacological tools like reserpine, amphetamine, tryptamine and tetrabenazine for determining their possible mechanism of action. Amongst the three indole compounds investigated, indole-3-(2-aminopropyl)-acetate (U-14 164E), indole-3(2-aminobutyl)-d-acetate (u-17 312E) and beta-phenethylhydrazine (phenelzine) produced complete antagonism to reserpine induced sedation, hypothermia as well as facilitation of convulsive seizures. Some of these features suggest that MAO inhibition might be a common mechanism of action of these indoles. The potentiation of CNS effects of tryptamine by these compounds is an outstanding feature of MAO inhibitors, while imipramine is ineffective. Qualitative differences between these indoles and imipramine are evident in the tetrabenazine test. The potentiation of amphetamine induced motor excitation and pentobarbitone narcosis has been explained.

Analgesia↗
PubMed1981

High pressure liquid chromatographic method for indole in shrimp: development of method and collaborative study.

A collaborative study on the determination of indole in shrimp was conducted in which a high pressure liquid chromatographic (HPLC) method and a spectrofluorometric method were compared with the AOAC gas-liquid chromatographic (GLC) method (18.075-18.078, 13th ed.). In the HPLC method, 10 g shrimp was blended with methanol, an internal standard was added, and the extract was filtered. Indole was separated on an octadecylsilane reverse phase column, using 60% MeOH-H2O, and quantitated with a fluorescence detector (excitation 280 nm, emission 330 nm) by comparing the indole peak height with that of an internal standard, 2-methyl-indole. Recoveries at a 25 micrograms/100 g level averaged 104% with a range of 90-127%, and at a level of 35 micrograms/100 g averaged 102% with a range of 93-112%. In the spectrofluorometric method, 25 g shrimp was extracted with 2% EtOAc-hexane. After several washes, indole was partitioned into a saturated NaCl-MeOH solution and its fluorescence was measured (excitation 280 nm, emission 332 nm). Recoveries at a 25 micrograms/100 g level averaged 93% with a range of 0-255% and at a level of 35 micrograms/100 g averaged 64% with a range of 0-107%. Recoveries obtained by the AOAC-GLC method at a level of 25 micrograms/100 g averaged 96% with a range of 81-116% and at a level of 35 micrograms/100 g averaged 101% with a range of 81-119%. The coefficients of variation were 20, 10, and 64% at a 25 micrograms/100 g level for the GLC method, the HPLC method, and the spectrofluorometric method, respectively. The HPLC method was adopted as official first action for indole levels in shrimp exceeding 1 microgram/100 g.

Animals↗
PubMed1981

Modified colorimetric method for determining indole in shrimp.

A modified spectrophotometric method for measuring indole in shrimp is described. The method was developed to eliminate the time-consuming steam distillation and expensive instrumentation required by the official AOAC methods. Indole is extracted with light petroleum from trichloroacetic acid-precipitated shrimp muscle. The extracted indole, soluble in light petroleum, is reacted and re-extracted with Ehrlich's reagent; indole in the form of a rose indole complex can be determined spectrophotometrically. When shrimp at various degrees of decomposition were analyzed for indole by the modified method as well as by the official AOAC colorimetric method, the correlation coefficient between the data from the 2 methods was 0.98.

Animals↗
PubMed2003

NMR structure of the (+)-CPI-indole/d(GACTAATTGAC)-d(GTCAATTAGTC) covalent complex.

We report the NMR solution structure of (+)-CPI-indole (CPI, 1,2,8,8a-tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one), an agent belonging to the CC-1065/duocarmycin family of antitumor compounds. This (+)-CPI-indole structure is covalently bound to d(G(1)ACTAATTGTC(11))-d(G(12)TCAATTAGTC(22)), a synthetic DNA duplex containing a high-affinity binding site. The three-dimensional structure has been determined by several cycles of restrained molecular dynamics calculations with a total of 563 NMR-derived constraints, both in vacuo and by using the generalized Born solvent continuum model. In-depth analysis of the structure of this ligand-DNA complex led to a detailed knowledge of the bound state conformation of the CPI-indole, the most simplified agent related to CC-1065 and duocarmycins, the parent members of a family of extremely potent antitumor compounds. Comparison of the CPI-indole bound conformation with those previously found for (+)-duocarmycin SA (DSA), its unnatural enantiomer (-)-DSA, and the demethoxylated analogue (+)-DSI in their DNA complexes provided additional evidence of the tight correlation between the catalytic effect exerted by DNA on the alkylation reaction and the extent of angular twist between the two planar heteroaromatic subunits of these agents. Additionally, comparison of the structural features of the DNA-bound state of a "naked" ligand, such as CPI-indole, with those of various other duocarmycin agents provided useful information for the interpretation of the observed effects on chemical reactivity of the different substitution patterns at the hemispheres of these types of complex.

Antineoplastic Agents, Alkylating↗
PubMed2005

Cascade alkenyl amination/Heck reaction promoted by a bifunctional palladium catalyst: a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides.

A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.

Journal Article↗
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↗
PubMed1981

5-methoxy-2-methyl-3-indole acetic acid, a metabolite and alkali hydrolysis product of indomethacin, inhibits platelet aggregation, in vivo.

Previous studies suggested that one of the hydrolysis products of indomethacin, either 4-chlorobenzoic acid or 5-methoxy-2-methyl-3-indole acetic acid, can inhibit platelet aggregation in vivo. If correct, this hypothesis explains the apparent action of indomethacin dissolved at high pH where hydrolysis rapidly occurs. Moreover, if the indole is the active product, the hypothesis in addition suggests a possible role for the indole following the use of indomethacin dissolved at lower pH, since the indole is also an important natural metabolite of indomethacin in man. We induced platelet aggregation in cerebral and mesenteric microvessels and inhibited this aggregation with the indole (25 mg/kg i.p. one hour before test). The 4-chlorobenzoic acid was inactive. The indole had a modest but statistically significant inhibitory effect in vitro, when added to platelet rich plasma stimulated to aggregate by arachidonic acid (0.5 mM). Thus the action of indomethacin dissolved at high pH is explained, and a pharmacologic action of a metabolite of indomethacin becomes a possibility.

Animals↗