Antagonism of 5-hydroxykynurenamine against serotonin action on platelet aggregation.
(1/135)
Serotonin induced an aggregation of human platelets, whereas 5-hydroxykynurenamine, produced from serotonin by the action of indoleamine 2,3-dioxygenase, did not cause any significant degree of platelet aggregation. 5-Hydroxykynurenamine specifically inhibited both a serotonin-induced aggregation of platelets and the potentiation of the ADP-induced platelet aggregation by serotonin. It did not, however, alter the profiles of the platelet aggregation induced by ADP, collagen, or adrenaline. The degree of inhibition was proportional to the time of preincubation of platelets with 5-hydroxykynurenamine, and to the concentration of 5-hydroxykynurenamine used. Available evidence indicated that 5-hydroxykynurenamine completed with serotonin for the same receptor sites. Studies with analogues of 5-hydroxykynurenamine indicated that the substitutions of 0-amino-benzyl moiety with hydroxy or methoxy groups were somewhat tolerated, whereas the masking of alkylamine moiety with N-acetylation completely lost the inhibitory activity. (+info)
Functional discovery via a compendium of expression profiles.
(2/135)
Ascertaining the impact of uncharacterized perturbations on the cell is a fundamental problem in biology. Here, we describe how a single assay can be used to monitor hundreds of different cellular functions simultaneously. We constructed a reference database or "compendium" of expression profiles corresponding to 300 diverse mutations and chemical treatments in S. cerevisiae, and we show that the cellular pathways affected can be determined by pattern matching, even among very subtle profiles. The utility of this approach is validated by examining profiles caused by deletions of uncharacterized genes: we identify and experimentally confirm that eight uncharacterized open reading frames encode proteins required for sterol metabolism, cell wall function, mitochondrial respiration, or protein synthesis. We also show that the compendium can be used to characterize pharmacological perturbations by identifying a novel target of the commonly used drug dyclonine. (+info)
In vitro biotransformation of xanthohumol, a flavonoid from hops (Humulus lupulus), by rat liver microsomes.
(3/135)
Xanthohumol (XN) is the major prenylated flavonoid of the female inflorescences (cones) of the hop plant (Humulus lupulus). It is also a constituent of beer, the major dietary source of prenylated flavonoids. Recent studies have suggested that XN may have potential cancer-chemopreventive activity, but little is known about its metabolism. We investigated the biotransformation of XN by rat liver microsomes. Three major polar metabolites were produced by liver microsomes from either untreated rats or phenobarbital-pretreated rats as detected by reverse-phase high-performance liquid chromatography analysis. Liver microsomes from isosafrole- and beta-naphthoflavone-pretreated rats formed another major nonpolar metabolite in addition to the three polar metabolites. As determined by liquid chromatography/mass spectrometry and (1)H NMR analyses, the three major polar microsomal metabolites of XN were tentatively identified as 1) 5"-isopropyl-5"-hydroxydihydrofurano[2",3":3',4']-2',4-dihydroxy-6'-methoxychalco ne; 2) 5"-(2"'-hydroxyisopropyl)-dihydrofurano[2",3":3',4']-2',4-dihydroxy-6'-methoxycha lcone; and 3) a derivative of XN with an additional hydroxyl function at the B ring. The nonpolar XN metabolite was identified as dehydrocycloxanthohumol. (+info)
In vitro glucuronidation of xanthohumol, a flavonoid in hop and beer, by rat and human liver microsomes.
(4/135)
Xanthohumol (XN) is the major prenylated flavonoid of hop plants and has been detected in beer. Previous studies suggest a variety of potential cancer chemopreventive effects for XN, but there is no information on its metabolism. The aim of this study was to investigate in vitro glucuronidation of XN by rat and human liver microsomes. Using high-performance liquid chromatography, two major glucuronides of XN were found with either rat or human liver microsomes. Release of the aglycone by enzymatic hydrolysis with beta-glucuronidase followed by liquid chromatography/mass spectrometry and nuclear magnetic resonance analysis revealed that these were C-4' and C-4 monoglucuronides of XN. (+info)
Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: a comparison of lidocaine, ropivacaine, and dyclonine.
(5/135)
BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD. RESULTS: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]). CONCLUSION: Both lidocaine and the new amide local anesthetic ropivacaine significantly attenuate histamine-induced bronchospasm. In contrast, dyclonine, despite its longer lasting and more intense local anesthesia, does not alter histamine-evoked bronchoconstriction and irritates the airways. Thus, airway anesthesia alone does not necessarily attenuate bronchial hyperreactivity. Other properties of inhaled local anesthetics may be responsible for attenuation of bronchial hyperreactivity. (+info)
Role of extraneuronal mechanisms in the termination of contractile responses to amines in vascular tissue.
(6/135)
1 The role of the uptake and release of agonist from extraneuronal sites in the termination of responses of rabbit aortic strips to amines was studied. 2 Strips were contracted with adrenaline or noradrenaline and after response plateau was reached, the muscle chambers were washed free of agonist and the relaxation in Krebs solution recorded. After inhibition of catechol-O-methyl-transferase, monoamine oxidase and neuronal uptake the relaxation rate was greatly prolonged. Evidence is provided that this very slow relaxation resulted from the accumulation of intact amine at extraneuronal sites during exposure to the agonist and its subsequent release past receptors due to a reversal of the concentration gradient after washout. 3 Pretreatment with the haloalkylamine, GD-131 (N-cyclohexylmethyl-N-ethyl-beta-chloroethylamine), an inhibitor of extraneuronal uptake, returned the slow relaxation rate after enzyme inhibition towards that of control strips. By blocking the extraneuronal transport of amines their accumulation at intracellular loci after enzyme inhibition was prevented. 4 The effects of GD-131 and 17beta-oestradiol on the relaxation rate of untreated strips contracted by adrenaline and noradrenaline confirmed that extraneuronal uptake to sites of enzymatic activity is the major mechanism terminating their action. 5 Inactivation of extraneuronal transport sites by GD-131 was prevented by protecting them with 17beta-oestradiol or normetanephrine during exposure to the haloalkylamine, pointing to a common site of action of these agents on a specific carrier system for amines. 6 Evidence is presented that the relaxation from contractions induced by histamine and 5-hydroxytryptamine also involves extraneuronal accumulation and release, probably by an uptake process which is identical to the one for catecholamines. (+info)
Modest radiosensitization of solid tumours in C3H mice by the hypoxic cell radiosensitizer NDPP.
(7/135)
The x-ray dose required to cure half the mice bearing first generation transplanted mammary carcinomata 150 days after irradiation was determined. NDPP proved to be a relatively poor radiosensitizer in mice, for although a maximum enhancement ratio of 1-3 was obtained when x-rays produced from a 1-4 MeVp electron accelerator were given between 10 and 17 min after the administration of NDPP, this was at a drug concentration sufficient to cause marked kidney abnormalities in 5-10% of the mice. (+info)
Cathinone (Khat) and methcathinone (CAT) in urine specimens: a gas chromatographic-mass spectrometric detection procedure.
(8/135)
A gas chromatographic-mass spectrometric procedure for detection of cathinone (Khat) and methcathinone (CAT) in urine was developed. The compounds were detected as 4-carboethoxyhexafluorobutyryl derivatives. Three ions for the drugs and two ions for the internal standards were monitored. The drugs were identified by comparing retention times and ion ratios with that of reference compounds. The concentrations were measured by using amphetamine-d6 as internal standard for cathinone and methamphetamine-d9 as internal standard for methcathinone, and were linear over the range of 25-5000 ng/mL for cathinone and 12.5-5000 ng/mL for methcathinone. The overall recoveries of cathinone and methcathinone were 86 and 78%, respectively. Intrarun and inter-run variations were < 20%. To verify that the drugs are not metabolites of over-the-counter medications, cathinone and methcathinone were tested in urine specimens collected from individuals who ingested phenylpropanolamine and pseudoephedrine. None of the specimens showed the keto-amines as the metabolic products. When the procedure was applied to test 66 amphetamine-immunoassay-positive specimens containing no amphetamine or methamphetamine, two specimens were found positive for cathinone (118 and 3266 ng/mL) and six specimens were found positive for methcathinone (13-91 ng/mL). (+info)