Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations of estrogen-inducible hepatic proteins and estrogen receptor proteins were studied in female rats after daily oral administration of vehicle control (0.5% carboxymethylcellulose), the nonsteroidal antiestrogens tamoxifen (TAM; 3, 11, or 45 mg/kg body weight), toremifene (TOR; 3, 12, or 48 mg/kg body weight), or the potent synthetic estrogen diethylstilbestrol (DES; 10 mg/kg body weight) for 1 and 3 months. Serum corticosterone levels were significantly reduced by TAM 11, TOR 12, and DES at 1 month and by TOR 48 and DES at 3 months. Serum ceruloplasmin levels were unchanged at 1 month except for a significant reduction with TOR 48 and a significant increase in the DES-treated group. After 3 months, all doses of TAM and TOR had significant reductions whereas DES had elevations even greater than those at 1 month. The activity of the enzyme alanine aminotransferase in the liver was increased by TAM, TOR, and DES at 1 and 3 months of treatment. Both TAM and TOR caused a slight reduction in cytosolic estrogen receptor protein after 1 month and significant reductions at 3 months. The nuclear estrogen receptor (nER) protein levels were significantly increased at 1 and 3 months for TAM and TOR; whereas DES treatment resulted in nER levels no different than controls. In summary, chronic (up to 3 months) administration of TAM and TOR results in qualitatively and quantitatively similar hormone-related effects on the female rat liver. Thus, other mechanisms must be investigated to ascertain the hepatoproliferative differences seen with TAM administration but not with TOR.
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PMID:The effects of diethylstilbestrol, tamoxifen, and toremifene on estrogen-inducible hepatic proteins and estrogen receptor proteins in female rats. 153 64

Exposure to a common phthalate, di(2-ethylhexyl)phthalate (DEHP), is associated with liver hyperplasia prior to the development of hepatocellular carcinoma in rodents. The exact mechanism of liver hyperplasia as well as tumorigenesis by this agent is not known. Since other lines of evidence point to estrogens as mediators of liver hyperplastic changes, we investigated whether DEHP exposure might alter hepatic estrogen metabolism and induce hyperplasia. Male Fischer 344 rats were fed either control or 1.2% DEHP-containing diets and sacrificed after 4, 8 and 16 weeks of exposure; activities of several sex hormone-responsive markers were measured. Rats fed DEHP had significantly increased serum estradiol levels, but hepatic activity of both cytosolic and nuclear estrogen receptor (ER) was significantly reduced. The serum content of ceruloplasmin, an estrogen-responsive protein synthesized by the liver, was also reduced, perhaps as a consequence of loss of ER activity. The rise in serum estradiol in DEHP-treated rats may be explained by the observation that these rats showed significant losses in hepatic activity of both a major male estrogen-metabolizing enzyme, estrogen 2-hydroxylase, and a male-specific estrogen-sequestering protein. In contrast to reductions in these activities, the expression of proliferating cell nuclear antigen and mRNAs for both ER and fos increased significantly as a result of exposure to DEHP. Our results suggest that changes in estrogen metabolism, receptor activity and activation of genes for cell proliferation are among the earliest metabolic alterations induced by DEHP. These changes together with the induced hyperplasia could play a crucial role in hepatocellular carcinoma development as a result of continuous exposure to DEHP.
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PMID:Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. 791 5

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.
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PMID:Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper. 1051 67

Men who chronically abuse alcohol may display a spectrum of endocrine abnormalities including hypogonadism and feminization, with elevated serum estradiol and low serum testosterone. We examined factors that may result in disruption of hepatic sex hormone homeostasis in alcohol-fed male rats and possible consequences of such changes. Rats were fed alcohol-containing or isocaloric diets for 30, 60, and 90 days. In alcohol-fed rats, serum testosterone levels and hepatic activity of 2 androgen-dependent estrogen metabolizing enzymes were reduced (P <.05) at all times, as was activity of androgen receptor. There was also a significant early and progressive decrease in testes/body ratio in alcohol-fed rats. Compared with this early decrease in testosterone-related parameters, there was a significant increase in serum estrogen levels (at 30 and 90 days, 132% and 168% of control values, respectively). An increase in serum ceruloplasmin, an estrogen-responsive liver protein, was apparent at 60 and 90 days, but not at 30 days of alcohol exposure, suggesting that hypogonadism precedes liver feminization. Hepatic estrogen receptor activity was decreased in alcohol-fed rats at 60 and 90 days, the latter despite elevated serum estrogen levels. Hepatic aromatase was slightly increased in alcohol-fed rats, an elevation probably not sufficient to account for observed increases in serum estrogen. Taken together, these data suggest that (1) alcohol induces profound reduction of serum testosterone, resulting in loss of androgen-regulated hepatic functions such as estrogen-metabolizing enzyme activity and activity of androgen receptors; and (2) such alcohol-induced hypogonadism precedes changes in hepatic sex hormone homeostasis and subsequent feminization.
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PMID:Hypogonadism precedes liver feminization in chronic alcohol-fed male rats. 1079 90

Astrocytes accumulate iron under chronic oxidative stress conditions in ageing and neurological disorders. The soybean isoflavone genistein possesses antioxidant properties and selective estrogen-like activities. Here, a possible role of genistein in modulation of iron transport was explored in glial cells. Genistein significantly increased iron export through estrogen receptor-beta-dependent p38 MAPK activation. Evidence is presented that this effect is associated to a p38 MAPK-triggered up-regulation of the iron export system made by ceruloplasmin and ferroportin-1, a pathway requiring activation of the transcription factor C/EBP.
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PMID:Genistein up-regulates the iron efflux system in glial cells. 2005 27