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PubMed1985

Effects of dietary indoles and isothiocyanates on N-nitrosodimethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone alpha-hydroxylation and DNA methylation in rat liver.

Dietary-related indoles, isothiocyanates, and the allyl isothiocyanate glucosinolate, sinigrin, were administered to F344 rats in the diet for 2 weeks (chronic protocol) or by gavage 2 h before sacrifice (acute protocol) and the effects of these pretreatments on the alpha-hydroxylation of two carcinogenic nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were evaluated. alpha-Hydroxylation was measured in vitro by quantitation of formaldehyde formation upon incubation of the nitrosamines with liver microsomes, and in vivo by quantitation of levels of 7-methylguanine and O6-methylguanine in hepatic DNA, 4 h after nitrosamine treatment. Compounds shown to be inhibitory in the in vitro assay were selected to be further evaluated using the in vivo assay. The results of the in vitro assays showed that indoles were inducers of the demethylation of both nitrosamines. Indole, L-tryptophan and indole-3-carbinol were strong inducers of NDMA and NNK demethylation, respectively. In contrast, isothiocyanates such as phenethyl isothiocyanate and phenyl isothiocyanate demonstrated a wide range of inhibitory activities toward demethylation of these nitrosamines in both the acute and chronic studies. Chronic, but not acute, pretreatment with sinigrin also caused a significant decrease in the demethylation of NDMA and NNK. In view of their promising inhibitory activities, the effects of phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin on the in vivo methylation of DNA by NDMA and NNK were evaluated. The results were parallel to those obtained in the in vitro assays. Phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin generally inhibited the formation of 7-methylguanine and O6-methylguanine in rat hepatic DNA. The results of this study suggest that these compounds could be anticarcinogenic to NDMA and NNK.

Animals↗
PubMed2003

A liquid chromatographic-tandem mass spectrometric method for the analysis of serotonin and related indoles in human whole blood.

This paper describes a high-performance liquid chromatographic-tandem mass spectrometric (HPLC-MS-MS) method for the determination of serotonin (5-HT) and the related indoles tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), indole-3-acetic acid (IAA), and indole-3-proprionic acid (IPA) in whole blood. Ionization was achieved by atmospheric pressure chemical ionization (APCI). The method uses a solvent gradient to achieve baseline separation of all analytes. Linearity was established for all components from 10 to 500 ng/mL, with the exception of TRP, which was calibrated from 0.4 to 20 microg/mL. Limits of quantitation were established that were well below the normal endogenous concentrations of 5-HT and its related indoles. Recoveries of 5-HT, TRP, 5-HIAA, IAA, and IPA were 95%, 91%, 98%, 79%, and 65%, respectively, from whole blood matrix and varied less than 2%. Serotonin, TRP, and IAA results were verified by cross-validation with an external laboratory using a previously validated HPLC method with fluorometric detection. A regression analysis of the two data sets resulted in correlation coefficients of 0.981, 0.964, and 0.987 for 5-HT, TRP, and IAA, respectively.

Chromatography, High Pressure Liquid↗
PubMed1994

Indolic compounds affect tryptophan binding to rat hepatic nuclei.

This study evaluates the effects of indolic or indole-related compounds on binding of L-tryptophan (saturable, stereospecific and of high affinity) to rat hepatic nuclei or nuclear envelopes. Addition of any one of many indolic or indole-related compounds, and particularly of 3-methylindole, does not inhibit in vitro binding of [3H]tryptophan to hepatic nuclear envelopes. However, when 3-methylindole (10(-10) to 10(-4) mol/L) is added in combination with unlabeled L-tryptophan (10(-4) mol/L), it diminishes the inhibitory effect of unlabeled L-tryptophan alone. Scatchard analysis of the binding affinities of in vitro [3H]tryptophan binding to hepatic nuclear envelopes using L-tryptophan in the absence or presence of 3-methylindole reveals similar dissociation constants (KD) under the two conditions, but the binding concentrations (Bmax) were greater in the combined group compared with that in the L-tryptophan alone group. Addition of 3-methylindole to liver before homogenization decreases specific [3H]tryptophan binding to nuclei compared with controls (without addition). L-Tryptophan tube-fed to rats with or without 3-methylindole administration increases in vitro hepatic protein synthesis compared with that of saline tube-fed controls. 3-Methylindole itself does not affect protein synthesis. Our report describes the effects of 3-methylindole on specific tryptophan binding to hepatic nuclear envelope receptor and discusses the possible implications thereof.

Animals↗
PubMed1977

Suppression of dibutylnitrosamine-induced bladder carcinomas in hamsters by dietary indole.

Effect of dietary indole on the urinary bladder tumorigenesis by chronic dibutylnitrosamine (DBN) treatment was evaluated in hamsters. In the first experiment, in which DBN-water and diet were given ad libitum, dietary indole significantly suppressed bladder tumor incidence. The inhibitory effect was more pronounced in males. In the second experiment, in which consumption of both diet and DBN-water was rigidly controlled by pair-feeding, dietary indole again significantly suppressed bladder tumor incidence; its effect was similar in both males and females. This suppressive effect of indole on bladder tumorigenesis contrasted markedly with its failure to suppress tumors at other sites such as nasal sinuses, trachea, esophagus, and fore-stomach.

Administration, Oral↗
PubMed1970

The timing of growth promotion and conversion to indole-3-acetic acid for auxin precursors.

Using a high resolution continuous recording technique, the length of the latent period preceding the growth response to two suspected precursors of indole-3-acetic acid (IAA) indole-3-acetonitrile (IAN), and indole-3-ethanol was studied in corn (Zea mays L.), wheat (Triticum aestivum L.), and peas (Pisum sativum L.). The timing of the conversion in vivo of these presumed precursors to IAA was also examined. In wheat the rate of conversion of IAN to IAA is rapid, and the latent period in the growth response to IAN is correspondingly short. In corn the rate of conversion in vivo of IAN to IAA is slow, and there is a long latent period in the growth response. In peas there is no conversion of IAN to IAA, and there is no measurable growth response to IAN. These data indicate that IAN is active in promoting growth only after conversion to IAA. This conclusion is strengthened by transport studies. Using a similar approach, we have also obtained data indicating that indole-3-ethanol is active only after conversion to IAA.

Ethanol↗
PubMed1983

The catalytic mechanism of tryptophan synthase from Escherichia coli. Kinetics of the reaction of indole with the enzyme--L-serine complexes.

The mechanism by which indole condenses with L-serine in the active site of tryptophan synthase was studied by the stopped-flow technique. The single turnover occurs by rapid binding of indole to the pre-formed enzyme--L-serine complex, followed by C--C bond formation, reprotonation of the alpha carbon carbanion of L-tryptophan, and its final release. The effects of isotopic substitution at C-3 of indole, of pH, and of the presence of indolepropanol phosphate on these processes were also studied. The mechanism of binding of indole complements the known mechanisms of binding of L-serine and L-tryptophan to give a detailed picture of the mechanism of catalysis. It invokes two competent species of enzyme--L-serine complexes, leading to a branched pathway for the central condensation process. The rates of dehydration of L-serine and reprotonation of the carbanion of L-tryptophan are probably limited by rearrangements at the active site. Analysis of absorption, fluorescence and circular dichroic spectra, as well as of published data on the stereoisomers obtained by reduction with borohydride, suggests that the rearrangement includes a reorientation of the pyridoxal phosphate C-4' atom. The mechanism provides a detailed framework for explaining all available information, including the activating effect of the alpha subunit on the reaction catalyzed by the beta 2 subunit.

Catalysis↗
PubMed2000

Involvement of naphthalene dioxygenase in indole-3-acetic acid biosynthesis by Pseudomonas putida.

Two variants of plant growth-promoting strain Pseudomonas putida BS1380 harboring the naphthalene degradative plasmid pBS2 and the recombinant plasmid pNAU64 that contains the genes encoding for naphthalene dioxygenase were constructed by conjugation. The ability of this strain to produce phytohormone indole-3-acetic acid from different carbon sources was studied. Indole-3-acetic acid synthesis by these transconjugants was 15-30 times as much in contrast to a wild-type strain with glucose as the sole carbon source. No difference was observed in other carbon or nitrogen sources. It is suggested that naphthalene dioxygenase is involved in the conversion of indole-3-pyruvic acid to indole-3-acetic acid.

Cloning, Molecular↗
PubMed1985

In vitro uptake and metabolism of [3H]indole compounds in the pineal organ of the pike. II. A radioautographic study.

In a previous radiobiochemical study [Falcón et al., 1985] it was demonstrated that the pineal organ of the pike incubated in vitro takes up and metabolizes [3H]serotonin and [3H]melatonin. Parallel to this experiment (present work), pineal organs were investigated by use of light and electron microscopic radioautography to investigate the cell types involved in indole metabolism. Irrespective of the tracer and experimental conditions used, the radioautographic reactions were mainly found in cone-like and modified photoreceptor cells of the pineal parenchyma. Taking into account the limits of the method used as well as previous data concerning the direct photosensitivity of the organ, the localization of exogenous indoles, and the localization and circadian variations of endogenous ones, it is concluded that the photoperiodic information is translated into both nervous and indolic signals in cone-like photoreceptor cells and into indolic signals in modified photoreceptor cells.

Animals↗
PubMed1988

Inhibitory actions of pineal indoles on steroidogenesis in isolated rat Leydig cells.

The inhibition elicited by pineal indoles on testosterone production by isolated rat Leydig cells could not be overcome by a maximally active dose of luteinizing hormone (LH), and dibutyryl-cAMP-induced steroidogenesis was also suppressed, suggesting that the indoles did not exert their effect through an interaction with LH receptors on Leydig cells. Pregnenolone-induced progesterone secretion was unaffected, indicating that the activity of 3 beta-dehydrogenase was not altered. Methoxytryptamine (MTN) at a dose of 1 mM decreased progesterone-induced 17 alpha-hydroxyprogesterone secretion by 50%, suggesting that the enzyme 17 alpha-hydroxylase was inhibited. The inhibition caused by other pineal indoles was either very slight or absent. MTN reduced 17 alpha-hydroxyprogesterone-induced androstenedione production by 65%, methoxytryptophol (MTOL) and melatonin (MEL) by 35%, and methoxyindoleacetic acid (MIAA) and hydroxyindoleacetic acid (HIAA) by 10%, revealing an inhibition of 17-20 desmolase. The reduction of androstenedione-induced testosterone production by MTN infers inhibition of 17-ketoreductase activity. However, testosterone production induced by either dehydroepiandrosterone or androstenedione was unaffected by other indoles. The data suggest that MTN inhibited 17 alpha-hydroxylase, 17-20 desmolase, and 17-ketoreductase while MEL, MTOL, MIAA, and HIAA inhibited only 17-20 desmolase. The highest potency of MTN in inhibiting enzymes on the testosterone biosynthestic pathway was reflected in its greatest inhibition of testosterone production. On the other hand, MIAA and HIAA had the lowest potency in inhibiting the enzymes and testosterone production while MEL and MTOL had intermediate potencies.

Animals↗
PubMed1989

Activity of melatonin and other pineal indoles on the in vitro synthesis of cortisol, cortisone, and adrenal androgens.

The in vitro effects of 13 indole compounds on the synthesis of glucocorticoids and of adrenal androgens in sheep adrenal glands has been studied from 11-deoxycortisol as a precursor. This work demonstrates the activating effect of some indole compounds on 11 beta-hydroxylase and 17,20-desmolase and the inhibitory effect of most of them on 11 beta-hydroxysteroid dehydrogenase. Three categories could be distinguished: 1) compounds without any effect (5-hydroxytryptophan, 5-hydroxytryptamine); 2) compounds moderately increasing (10-30% as compared with controls) cortisol yields (tryptamine, melatonin, 6-hydroxymelatonin, 5-methoxytryptophol, indomethacin); and 3) compounds markedly increasing (80-100%) cortisol yields (5-methoxyindole acetic acid, 5-hydroxyindole acetic acid, 2-methylindole, 5-hydroxytryptophol, N-acetyl-5-hydroxytryptamine). In fact, since most of the studied indoles reduced 11 beta-hydroxysteroid dehydrogenase activity, the actual activation of cortisol synthesis was four to five times less. Lastly, all the studied compounds, but melatonin, increased the activity of 17,20 desmolase as seen from 11 beta-hydroxyandrostenedione and 11-ketoandrostenedione yields. The possible in vivo effects of the indoles for therapeutic use needs further studying.

Adrenal Glands↗
PubMed1993

Antiproliferative effect of pineal indoles on cultured tumor cell lines.

The in vitro antiproliferative action of pineal indoles on several tumor cell lines including melanoma (B16), sarcoma (S180), macrophage-like cell line (PU5), fibroblasts (3T3), and choriocarcinoma (JAr) was examined by measuring the incorporation of 3H-thymidine by the tumor cells, and, in the case of melanoma cells, by also measuring the incorporation of 3H-leucine and 3H-uridine. Uptake of crystal violet was used to assess the viability of the tumor cells. The order of inhibitory potency of the indoles was found to be methoxytryptamine > melatonin, methoxytryptophol, hydroxytryptophol, and methoxyindoleacetic acid > serotonin and hydroxyindoleacetic acid. The possibility of an adverse effect of the indoles on the viability of normal cells was also investigated by employing a primary culture of rat hepatocytes. The release of glutamate-oxaloacetate transaminase by hepatocytes was not affected by the indoles, although the release of glutamate-pyruvate transaminase was increased to a small extent and the uptake of crystal violet was slightly inhibited.

3T3 Cells↗
PubMed1982

Differences in susceptibilities of species of the Bacteroides fragilis group to several beta-lactam antibiotics: indole production as an indicator of resistance.

Clinical isolates of the members of the Bacteroides fragilis group differ markedly in their susceptibilities to a variety of beta-lactam antibiotics, including cefoperazone, moxalactam, cefotaxime, cefoxitin, cefamandole, cephalothin, cefazolin, and carbenicillin, as determined by dilution techniques. The minimum concentrations required to inhibit at least 50% of the strains tested (MIC50) for the entire B. fragilis group were lowest with moxalactam and cefoxitin, 4 and 8 micrograms/ml, respectively, whereas the MIC90S of cefoperazone, cefotaxime, moxalactam, cefoxitin, and carbenicillin were equivalent (64 micrograms/ml); the MIC90S of cefamandole, cephalothin, and cefazolin were higher. Indole-positive members of the group (B. ovatus, B. thetaiotaomicron, and B. uniformis) were significantly more resistant to every antibiotic tested than were indole-negative members (B. fragilis, B. distasonis, and B. vulgatus). In a 6-month survey of clinical laboratory data, indole-positive strains comprised 40% of the B. fragilis group isolates and 22% of all Bacteroides isolates; B. fragilis was the most common species isolated (23%). The increased use of second-generation and the introduction of third-generation cephalosporins may dictate that clinical microbiology laboratories routinely identify members of the B. fragilis group as to species or, alternatively, test for indole production in addition to performing more extensive susceptibility testing.

Anti-Bacterial Agents↗
PubMed1972

Characterization of indole-positive Proteus mirabilis.

Thirteen indole-producing, swarming strains of Proteus were identified by additional biochemical testing as being Proteus mirabilis. These strains were characterized by 40 biochemical tests and by susceptibility testing to 11 antibiotics. All produced ornithine decarboxylase and were susceptible to members of the penicillin-cephalosporin groups of antibiotics. These indole-positive strains are similar to indole-negative P. mirabilis and are distinctly different from P. vulgaris. For greatest accuracy and to insure greatest clinical relevancy, P. mirabilis and P. vulgaris should be distinguished from one another in the laboratory by performing both the indole and ornithine decarboxylase tests.

Ampicillin↗
PubMed2004

Molecular basis of the indole-negative reaction in Shigella strains: extensive damages to the tna operon by insertion sequences.

The molecular basis of the loss of tryptophan utilization (indole-negative phenotype) of Shigella strains, in effect clones of Escherichia coli, was investigated. Analysis of the tna operon of 23 Shigella strains representing each of the indole-negative serotypes revealed that insertion sequence-mediated insertion and/or deletions damaged the tna operon, leading to inability to convert tryptophan to indole. These events differ for cluster 1, cluster 3, and the outlier Shigella strains, confirming our previous observation of independent origins of these lineages from within E. coli. Parallel loss of the trait and prevalence of indole-negative strains suggest that the trait is deleterious in Shigella strains and advantages those without it.

DNA Transposable Elements↗
PubMed1980

Evaluation of Urea-motility-indole medium for recognition and differentiation of Salmonella and Shigella species in stool cultures.

A semisolid urea-motility-indole medium designed for detection in Enterobacteriaceae of urease activity, motility, and indole production in one tube was prepared and evaluated. The formulation of the medium was similar to that of Christensen urea agar, but the agar concentration was 0.2%, and 1% tryptone was added. Results with 687 strains of Enterobacteriaceae were the same as those obtained with standard test media (98% overall agreement). The urea-motility-indole medium was also used in combination with Kligler iron agar for the recognition and differentiation of Salmonella and Shigella species from colonies picked from plating media in fecal cultures. This combination was compared with the combination of Kligler iron agar and lysine iron agar with 507 strains of non-lactose-fermenting Enterobacteriaceae. Although both combinations enabled the presumptive recognition and differentiation of Salmonella and Shigella species, an analysis of data indicated that the combination of Kligler iron agar and urea-motility-indole medium performed better than the combination of Kligler iron agar and lysine iron agar in detecting Salmonella and Shigella species.

Culture Media↗
PubMed1982

Differentiation of Haemophilus spp. in Respiratory isolate cultures by an indole spot test.

Indole spot tests using isolated, nonhemolytic colonies of Haemophilus species were positive for 90 of 151 (60%) respiratory isolates of Haemophilus influenzae, whereas 67 to 72 (93%) isolates of H. influenzae from cerebrospinal fluid and blood specimens were indole positive. Only 4 of 117 (3%) Haemophilus parainfluenzae isolates were positive for indole spot tests. Thus, indole-positive, nonhemolytic Haemophilus isolates in respiratory cultures can be presumptively identified as H. influenzae.

Bacteriological Techniques↗
PubMed2000

A novel class of inhibitors for human steroid 5alpha-reductase: synthesis and biological evaluation of indole derivatives. II.

In a search for novel nonsteroidal inhibitors of human prostatic 5alpha-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxyl-3-chlorobenzoic acid (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC50 value of 0.44 nM. 3-Chloro-4-[[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy]benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5alpha-reductase with IC50 values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.

5-alpha Reductase Inhibitors↗
PubMed2005

Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid.

In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.

Acetates↗