Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of chronic MtTW15 pituitary adenoma implantation on beta-adrenergic responsiveness, cardiac beta-adrenoreceptors, and muscarinic receptors were studied in the rat. Five weeks after s.c. administration of tissue fragments of the MtTW15 adenoma, there was a 51 and 20% increase in the heart weight and body weight, respectively, and a 49-fold increase in the serum prolactin level as compared to the controls. At this time there was also an attenuation in the adenoma-bearing group of the ability of isoproterenol to produce a dipsogenic response and to increase the heart rate. In contrast, isoproterenol stimulated cardiac ornithine decarboxylase (ODC) activity 4.2-fold in both the control and adenoma-bearing groups. There was no change between the two groups in the cardiac ventricular beta-adrenoreceptor or muscarinic receptor concentration as measured by specific (-)-[125I]iodocyanopindolol (CYP) and (-)-[3H]quinuclidinyl benzilate (QNB) respectively. In addition, the concentrations of isoproterenol and carbachol required to inhibit by 50% (IC50) [125I]CYP and [3H]QNB binding, respectively, in the absence of 5'-guanylylimidodiphosphate (Gpp(NH)p) were not different between the two groups. In the presence of Gpp(NH)p, the isoproterenol IC50 value was not different between the two groups, whereas the carbachol IC50 value was increased slightly in the adenoma-bearing group. The data indicate that chronic MtTW15 adenoma implantation attenuated beta-mediated dipsogenic and heart rate responses but had little or no effect on cardiac ODC activity or cardiac autonomic receptor concentrations and agonist binding properties.
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PMID:Beta-adrenergic responsiveness and cardiac autonomic receptors after implantation of the MtTW15 pituitary adenoma in the rat. 303 64

4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine (DMP 904) is a potent and selective antagonist of corticotropin releasing factor receptor-1 (CRF1 receptor) with an efficacious anxiolytic profile in preclinical animal models. In subchronic toxicity studies in Sprague-Dawley rats, DMP 904 produced thyroid follicular cell hypertrophy and hyperplasia, and a low incidence of follicular cell adenoma. The current investigations were designed to determine the mode of action by which DMP 904 disrupts thyroid homeostasis in male rats. Five-day treatment with DMP 904 (300 mg/kg/day) dramatically lowered serum thyroxine (T4) to levels below detectable limits (< 1 microg/dl) by 72 h, with concurrent decreases in triiodothyronine (T3, about a 70% decrease) and increases in thyroid stimulating hormone (TSH; about a three-fold increase). DMP 904 increased [125I]T4 total body clearance (Cl tb) (38.21 +/- 10.45 ml/h) compared to control (5.61 +/- 0.59 ml/h) and phenobarbital-treated rats (7.92 +/- 1.62 ml/h). This increase in Cl(tb) was associated with a significant increase in biliary clearance (Cl bile) of unconjugated [125I]T4 (nearly 80-times control rates) and increased liver:blood ratios of T4, suggestive of enhanced hepatic uptake of T4. A single dose of DMP 904 (200 mg/kg) increased mRNA levels of hepatic cytochrome P450s (CYP 3A1 and CYP 2B1) and UDP-glucuronosyltransferases (UGT 1A1 and UGT 1A2). DMP 904 also induced mRNAs of the canalicular transporter, multi-drug resistance protein-2 (Mrp2) and sinusoidal transporters, organic anion transporting proteins (Oatp1 and Oatp2) within 24 h. Western blot analysis confirmed DMP 904 related increases in Oatp2 protein expression. Collectively, these data suggest that DMP 904 is an agonist of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that the decreased serum levels of T4 and T3 resulted from increased hepatobiliary clearance. However, DMP 904 is distinguished from other compounds associated with similar effects on thyroid hormone homeostasis because its effects were primarily related to increased biliary excretion of unconjugated T4.
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PMID:Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats. 1567 46

Recently we reported that the occurrence of lung adenoma caused by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was completely prevented by pretreatment of female A/J mice with 8-methoxypsoralen, a potent inhibitor of cytochrome P450 (P450 or CYP) 2A [Takeuchi et al. (2003) Cancer Res., 63, 7581-7583]. Thus, the aim of this study was to confirm that 8-methoxypsoralen exhibits chemopreventive effects by inhibiting CYP2A in the mouse lung. The involvement of CYP2A in the metabolic activation of NNK in the lung was first evidenced by the fact that the mutagenic activation of NNK by mouse lung microsomes was inhibited by 8-methoxypsoralen, coumarin and antibodies to rat CYP2A1. Supporting this, the mutagenic activation of NNK was efficiently catalyzed by mouse CYP2A4 and CYP2A5 co-expressed with NADPH-P450 reductase in a genetically engineered Salmonella typhimurium YG7108. The expression of mRNA for CYP2A5, but not for CYP2A4 or CYP2A12, in the mouse lung was proven by reverse transcriptase-polymerase chain reaction, probably indicating that CYP2A5 present in the mouse lung was involved in the metabolic activation of NNK. In accordance with these in vitro data, treatment of gpt delta transgenic mice with 8-methoxypsoralen prior to NNK completely inhibited the mutation of the gpt delta gene. The in vivo chemopreventive effects of 8-methoxypsoralen towards NNK-induced adenoma was seen only when the agent was given to female A/J mice prior to, but not posterior to, NNK, lending support to the idea that NNK is activated by CYP2A5 in the mouse lung as an initial step to cause adenoma. The inhibition by 8-methoxypsoralen of NNK-induced adenoma was seen in a dose-dependent manner: the dose to show apparent 50% suppression was calculated to be 1.0 mg/kg. To our surprise, CYP2A protein(s) was expressed in the lesion of NNK-induced lung adenomas, probably suggesting that 8-methoxypsoralen could inhibit the possible occurrence of further mutation of the adenoma cells induced by NNK. Based on these lines of evidence, we propose that 8-methoxypsoralen inhibits the CYP2A5-mediated metabolic activation of NNK in the mouse lung, leading to the prevention of NNK-induced adenoma.
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PMID:Mechanisms of chemopreventive effects of 8-methoxypsoralen against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung adenomas. 1595 17

Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype toward SM-12502, we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Using genetically engineered Salmonella typhimurium expressing a human CYP, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Taking these results into consideration, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk of tobacco-related lung cancer. In accordance with our hypothesis, our epidemiological studies indicated that smokers homozygous for the CYP2A6*4C allele showed much lower odds ratios toward cancer risk. Other mutant alleles reducing the CYP2A6 activity, besides CYP2A6*4C, also reduced the risk of lung cancer in smokers, particularly of squamous-cell carcinoma and small-cell carcinoma, both smoking-related cancers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.
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PMID:Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. 1617 98

In patients with primary aldosteronism (PA), it is fundamental to distinguish between subtypes that benefit from different treatment. The authors describe difficulties in differential diagnosis in a case of 46 year old women with PA and two strokes in the past. Based on high plasma and urine aldosterone concentration, low plasma renin activity (PRA), very high aldosterone/PRA ratio and unilateral macroadenoma detected in computed tomography, aldosterone producing adenoma was diagnosed and the patient was performed unilateral adrenalectomy. Despite the surgical treatment the patient still presented with clinical and biochemical PA symptoms. Moreover, histological examination suggested adrenal hyperplasia, and laboratory tests were typical for glucocorticoid-remediable aldosteronism. Unfortunately, we didn't find a chimeric CYP 11beta1/CYP 11beta2 gene. Finally, bilateral adrenal hyperplasia was diagnosed and medical treatment with aldosterone antagonist was initiated.
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PMID:[The difficulties in differential diagnosis of primary aldosteronism subtypes in women with strokes at a young age]. 2004 69