Protection against Trp-P-2 mutagenicity by purpurin: mechanism of in vitro antimutagenesis.
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Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) is a natural pigment isolated from madder root (Rubia tinctorum) which inhibits the mutagenicity of a number of heterocyclic amines in the Ames mutagenicity test. Two effects were observed in the presence of purpurin. The rate of degradation of 3-hydroxyamino-1-methyl-5H-pyrido inverted question mark4,3-bindole inverted question markTrp-P-2(NHOH) at neutral pH was increased. The major product of this purpurin-dependent degradation was identified as the parent amine 3-amino-1-methyl-5H-pyrido inverted question mark4,3-bindole (Trp-P-2). Secondly, the rate of Trp-P-2 N-hydroxylation, the major route of bioactivation, by PCB-treated rat hepatic microsomes was markedly decreased. Cytochrome P450-dependent O-dealkylation of methoxy-, ethoxy- and pentoxyresorufin by these microsomes was also significantly inhibited by purpurin. The nature of this inhibition was competitive. Spectrophotometric investigations suggest no direct interaction between Trp-P-2 and purpurin. Furthermore, no evidence for Trp-P-2 binding was observed with carminic acid, a structural analog of purpurin, when it was immobilized on omega-aminohexyl agarose. Therefore, in vitro the proposed mechanism by which purpurin protects against heterocyclic amine-induced mutagenesis involves competitive inhibition of cytochrome P450-dependent bioactivation and accelerated degradation of the N-hydroxylamine to the parent amine. (+info)
Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers.
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BACKGROUND: Alosetron is a potent and selective 5-HT3 receptor antagonist, which has been shown to be beneficial in the treatment of female patients with non-constipated irritable bowel syndrome. AIMS: To investigate the effect of alosetron on whole gut, small bowel and colonic transit in patients with irritable bowel syndrome (Study 1) and healthy volunteers (Study 2). SUBJECTS: Thirteen patients with irritable bowel syndrome and 12 healthy volunteers. METHODS: Both studies were randomized, double-blind, placebo-controlled with a two-way crossover design, in which each subject received alosetron (2 mg b.d. administered orally) or placebo for 8 days. Mean whole gut transit was determined from the excretion of radio-opaque markers; small bowel transit was determined from rise in breath hydrogen after a meal; and colonic transit and segmental transit were evaluated from abdominal X-ray. In addition, colonic transit was calculated by subtracting small bowel transit time from whole gut transit time. RESULTS: Alosetron increased colonic transit time by prolonging left colonic transit in both patients with irritable bowel syndrome and controls. This resulted in a tendency for the whole gut transit to be delayed in irritable bowel syndrome patients (P=0.128), which was confirmed in controls (P=0.047). CONCLUSION: Alosetron delays colonic transit by prolonging left colonic transit. These results add to the body of evidence suggesting that alosetron should have a therapeutic role in patients with non-constipated irritable bowel syndrome. (+info)
In vitro bioactivation of N-hydroxy-2-amino-alpha-carboline.
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2-Amino-alpha-carboline (A alpha C) is a mutagenic and carcinogenic heterocyclic amine present in foods cooked at high temperature and in cigarette smoke. The mutagenic activity of A alpha C is dependent upon metabolic activation to N-hydroxy-A alpha C (N-OH-A alpha C); however, the metabolism of N-OH-A alpha C has not been studied. We have synthesized 2-nitro-alpha-carboline and N-OH-A alpha C and have examined in vitro bioactivation of N-OH-A alpha C by human and rodent liver cytosolic sulfotransferase(s) and acetyltransferase(s) and by recombinant human N-acetyltransferases, NAT1 and NAT2. The sulfotransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol exhibited large inter-individual variation (0.5-75, n = 14) and was significantly higher than bioactivation of N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). Correlation and inhibition studies suggested that the isoform of sulfotransferase primarily responsible for bioactivation of N-OH-A alpha C in human liver cytosol is SULT1A1. O-Acetyltransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol also exhibited large inter-individual variation (16-192, n = 18). In contrast to other N-hydroxy heterocyclic amines, which are primarily substrates only for NAT2, both NAT1 and NAT2 catalyzed bioactivation of N-OH-A alpha C. The rate of bioactivation of N-OH-A alpha C by both NAT1 and NAT2 was significantly higher than that for N-OH-PhIP. In rat and mouse liver cytosols, the level of sulfotransferase-dependent bioactivation of N-OH-A alpha C was similar to the level in the high sulfotransferase activity human liver cytosol. The level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in rat liver cytosol was also comparable with that in the high acetyltransferase activity human liver cytosol. However, the level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in mouse liver cytosol was comparable with that in the low acetyltransferase activity human liver cytosol. In contrast to N-OH-PhIP, bioactivation of N-OH-A alpha C was not inhibited by glutathione S-transferase activity; however, DNA binding of N-acetoxy-A alpha C was inhibited 20% in the presence of GSH. These results suggest that bioactivation of N-OH-A alpha C may be a significant source of DNA damage in human tissues after dietary exposure to AalphaC and that the relative contribution of each pathway to bioactivation or detoxification of N-OH-A alpha C differs significantly from other N-hydroxy heterocyclic or aromatic amines. (+info)
Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome.
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BACKGROUND: Alosetron, a 5-HT3-receptor antagonist, relieves abdominal pain and improves bowel function in non-constipated, female patients with irritable bowel syndrome. 5-HT3 antagonists delay colonic transit, increase colonic compliance, and increase small intestinal water absorption. AIM: To evaluate the effects of alosetron on gastrointestinal and colonic transit, rectal compliance and rectal sensation in irritable bowel syndrome. METHODS: A double-blind, placebo-controlled, two-dose study of alosetron was performed in 25 non-constipated irritable bowel syndrome patients, with paired studies before and after 4 weeks of treatment with placebo (n=5), 1 mg alosetron (n=10) or 4 mg (n=10) alosetron b.d. Gastrointestinal and colonic transit were measured by scintigraphy. Rectal compliance and sensation were assessed by rectal balloon distention with a barostat. RESULTS: There was a trend (P=0.06) for 1 mg alosetron to increase rectal compliance (median pressure at half maximum volume 11 mmHg after alosetron vs. 15.6 mmHg before alosetron). The 1 mg b.d. alosetron dose non-significantly retarded proximal colonic transit. Alosetron and placebo reduced sensory scores relative to baseline values; none of the changes induced by alosetron was significant relative to placebo. CONCLUSIONS: Alosetron had no significant effect on gastrointestinal transit or rectal sensory and motor mechanisms in non-constipated irritable bowel syndrome patients in this study. Alosetron's effects on colonic sensorimotor function and central sensory mechanisms deserve further evaluation. (+info)
Cytochrome P4501A1-inhibitory action of antimutagenic anthraquinones in medicinal plants and the structure-activity relationship.
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We have earlier found that flavones and flavonols in vegetables specifically inhibited one of the carcinogenesis-related enzymes, cytochrome P450 (CYP) 1A1, and subsequently suppressed the mutagenicity of food-derived carcinogens. In this study, we explored other candidates for the enzyme inhibitor in Chinese medicinal plants. Some of them were antimutagenic toward 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). For example, Rheum officinale contained large amounts of anthraquinones as the active compounds, 3.4 mg of emodin, 2.1 mg of chrysophanol and 1.8 mg of rhein in 10 g of dry matter. Anthraquinones showed similar IC50 values for antimutagenicity against Trp-P-2 to those for inhibition of the N-hydroxylation activity of CYP1A1 toward Trp-P-2, indicating that the antimutagenicity was attributable to CYP inhibition. The structure-activity relationships were then examined with 14 commercial chemicals, and it was found that the interaction with an enzyme required three rings and an oxygen group in the side ring. This characteristic is similar to that of flavones and flavonols. (+info)
Effect of Streptococcus thermophilus on the trp-P-1 level in the blood.
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We examined the 3-amino-1,4-dimethyl-5H-Pyrido-[4,3-b]indole (Trp-P-1) concentration in the blood after administering Trp-P-1 (0.25 mg/ml) with or without Streptococcus thermophilus 1131 cells (10 mg/ml) to rats. The Trp-P-1 concentration in the blood from the portal vein was significantly lower in the rats that had been administered with Trp-P-1 with the strain 1131 cells than without them. However, there was no difference in the Trp-P-1 concentration in the blood taken from the abdominal aorta of these rats. (+info)
Antagonism of the discriminative stimulus effects of positive gamma-aminobutyric acid(A) modulators in rhesus monkeys discriminating midazolam.
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The extent to which individual subtypes of benzodiazepine receptors are functionally independent has not been elucidated in vivo. This study used apparent pA(2) analysis to test the hypothesis that a single receptor subtype mediates the discriminative stimulus effects of midazolam, triazolam, and diazepam, three positive gamma-aminobutyric acid(A) (GABA(A)) modulators. Four rhesus monkeys discriminated 0.56 mg/kg midazolam from vehicle under a fixed-ratio 5 schedule of stimulus-shock termination. Midazolam, triazolam, and diazepam increased responding on the midazolam-appropriate lever. The neutral GABA(A) modulator flumazenil shifted dose-effect curves for triazolam and diazepam to the right, and the negative GABA(A) modulators Ro 15-4513 and ethyl beta-carboline-3-carboxylate (beta-CCE) shifted dose-effect curves for midazolam and triazolam to the right. Slopes of Schild plots for flumazenil and Ro 15-4513 conformed to unity. The apparent pA(2) values were 7.41 and 7.69 for flumazenil in combination with triazolam and diazepam, respectively, and 7.53 and 6.88 for Ro 15-4513 in combination with midazolam and triazolam, respectively. The slope of the Schild plot for beta-CCE in combination with midazolam deviated from unity. Slopes of Schild plots obtained with flumazenil and Ro 15-4513 support the notion that a single benzodiazepine receptor subtype mediates the effects of midazolam, triazolam, or diazepam. The similarity in apparent pA(2) values for flumazenil in combination with triazolam and diazepam or for Ro 15-4513 in combination with midazolam and triazolam suggests that the same subtype mediates the effects of these positive modulators. In contrast, beta-CCE and midazolam do not appear to interact in a simple, competitive manner. (+info)
The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys.
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Stress exposure impairs the cognitive functioning of the prefrontal cortex (PFC). Previous research has examined the dopamine (DA) D1 receptor mechanisms underlying this response. The current study performed a preliminary examination of the role of D4 receptor mechanisms by determining whether the selective D4 receptor antagonist, PNU-101387G, could prevent stress-induced working memory deficits in monkeys. Animals were tested on the delayed response task following treatment with PNU-101387G (0 or 0.1-0.8 mg/kg, 60-min pretreatment), and the pharmacological stressor, FG7142 (0 or 0.2 mg/kg, 30-min pretreatment). FG7142 significantly impaired delayed response performance relative to vehicle; PNU-101387G pretreatment produced a dose-related reversal of the FG7142 response. PNU-101387G had no significant effects on its own, but there were trends toward improvement at low doses and impairment at higher doses. Further studies in a larger number of animals appear warranted. These preliminary findings suggest that D4 receptor mechanisms contribute to stress-induced cognitive dysfunction. (+info)