Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ketoconazole is an imidazole derivative used as an antimycotic agent with reported effects on the endocrine system, but very little is known about its possible actions on thyroid function. Our purpose was to study the influence of this substance on the basal and TSH-stimulated iodide uptake in the rat thyroid cell strain FRTL-5. Ketoconazole (1-50 mumol/l) was shown to slightly increase the basal iodide uptake but, at higher concentrations (75-100 mumol/l), it sharply decreased iodide uptake below the basal levels. When the cells were cultured under bTSH stimulation (30 UI/l), the inhibitory effect of ketoconazole was exerted at concentrations as low as 25 mumol/l. This inhibition was observed even if it was added to the culture medium immediately before the Na125I addition. Forskolin, a stimulator of adenylate cyclase activity, was unable to prevent the iodide uptake inhibition. Low doses of ketoconazole increased cAMP concentrations. In the presence of TSH this effect was more evident in an inverse dose-dependent way. Because of its dual action, it can be assumed that ketoconazole could influence the iodide uptake in the FRTL-5 cells through more than one mechanism.
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PMID:Effects of ketoconazole on the iodide uptake by FRTL-5 cells. 133 1

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.
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PMID:Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse. 189 Aug 39

Cyclooxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The overexpression of cyclooxygenase-2 has been reported in skin cancer cells, and may be involved in carcinogenesis. Prostaglandin E2, the end product of cyclooxygenase-2-induced catalysis, autoamplifies the cyclooxygenase-2 expression. It is suggested that an anti-mycotic drug, ketoconazole may inhibit carcinogenesis. We herein investigated if ketoconazole may inhibit prostaglandin E2-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. Ketoconazole suppressed prostaglandin E2-induced cyclooxygenase-2 protein and mRNA expression and promoter activation in A-431; the suppressive effects of ketoconazole were counteracted by cyclic adenosine monophosphate analog. Analyses using deleted or mutated cyclooxygenase-2 promoters revealed that cyclic adenosine monophosphate response element (- 59 to - 53 bp) on the promoter was involved in prostaglandin E2-induced stimulation and ketoconazole-induced inhibition of the promoter activity. Electrophoretic mobility shift assays indicated that cyclic adenosine monophosphate response element binding protein and activating transcription factor-1 may constitutively bind to cyclic adenosine monophosphate response element on cyclooxygenase-2 promoter. Prostaglandin E2 increased the proportion of phosphorylated forms among total bound cyclic adenosine monophosphate response element binding protein/activating transcription factor-1, and the effect was suppressed by ketoconazole. Prostaglandin E2 induced the phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor-1, and the phosphorylation was suppressed by cyclic adenosine monophosphate-dependent protein kinase (protein kinase A) inhibitor, indicating protein kinase A-mediated phosphorylation. Ketoconazole suppressed the prostaglandin E2-induced phosphorylation of cyclic adenosine monophosphate response element binding protein/activating transcription factor-1. Prostaglandin E2 increased intracellular cyclic adenosine monophosphate level by activating adenylate cyclase in A-431, and the increase was suppressed by ketoconazole. These results suggest that ketoconazole may suppress prostaglandin E2-induced cyclooxygenase-2 expression by inhibiting the cyclic adenosine monophosphate signal in A-431, and stress its anti-cancer effect.
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PMID:Ketoconazole suppresses prostaglandin E(2)-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. 1216 41

We previously reported that antimycotic agent ketoconazole suppressed interleukin-4 production in T cells from patients with atopic dermatitis. We herein studied if ketoconazole may suppress B cell IgE class switching. Interleukin-4 plus anti-CD40-induced IgE secretion was enhanced in peripheral blood surface IgE- B cells from atopic dermatitis patients compared to those from normal donors, and the secretion was inhibited by ketoconazole. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced germline and mature epsilon transcripts in surface IgE- B cells. Ketoconazole also inhibited interleukin-4 plus anti-CD40-induced activation of germline epsilon promoter in human Burkitt lymphoma Ramos cells. The regions -171/-155 bp containing CCAAT/enhancer-binding protein element and -155/-109 bp containing Stat6 and nuclear factor kappaB elements were required for the ketoconazole-induced inhibition of the germline epsilon promoter activity. Ketoconazole inhibited interleukin-4 plus anti-CD40-induced enhancer activities of CCAAT/enhancer-binding protein and nuclear factor kappaB, and those of composite elements of CCAAT/enhancer-binding protein/Stat6 or of Stat6/nuclear factor kappaB, but did not alter that of Stat6 in Ramos cells. cAMP analog reversed the inhibitory effects of ketoconazole on interleukin-4 plus anti-CD40-induced IgE secretion, germline and mature epsilon transcripts, and epsilon germline promoter activation. Interleukin-4 plus anti-CD40 increased intracellular cAMP by activating cAMP-synthesizing adenylate cyclase in surface IgE- B cells, and the increase was greater in the cells from atopic dermatitis patients than in those from normal donors. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced activation of adenylate cyclase in surface IgE- B cells. These results suggest that ketoconazole may suppress interleukin-4 plus anti-CD40-induced B cell IgE class switching by inhibiting cAMP signal, and stress its prophylactic effects on allergic diseases.
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PMID:Ketoconazole suppresses interleukin-4 plus anti-CD40-induced IgE class switching in surface IgE negative B cells from patients with atopic dermatitis. 1223 May