Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to elucidate the effects of estrogen on polyamine metabolism in lipopolysaccharide (LPS)-treated mice, we assayed polyamine content and the activity of spermidine/spermine N1-acetyltransferase (SAT) and ornithine decarboxylase (ODC) in some organs. LPS elevated N1-acetylspermidine levels in the liver and lung and putrescine levels in the liver, lung and spleen. LPS increased the activity of ODC at 6 h and that of SAT at 12 h in the liver. When estradiol-17 beta was simultaneously administered with LPS, the maximum increase in hepatic N1-acetylspermidine levels was found 6 h earlier than in the LPS control. Likewise, the peak of the hepatic SAT activity after LPS-treatment was observed 6 h earlier in the estradiol-17 beta-treated mice than in the LPS control. No such effect of estradiol-17 beta was found in the lung and spleen. The LPS-induced ODC activity was not affected by estradiol-17 beta in the liver, lung or spleen. Estrone and 16 beta-ethylestradiol (an anti-estrogen) were also effective in enhancing the LPS-induced elevation of N1-acetyl-spermidine and putrescine in the liver, while both diethylstilbestrol, which has a potent estrogenic activity without steroid structure and estradiol-17 alpha (a non-estrogenic isomer of estradiol-17 beta) were without effect. Tamoxifen (an estrogen receptor antagonist) did not suppress the estrogen-induced increase in hepatic N1-acetylspermidine levels.
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PMID:Estradiol-17 beta modifies the induction of spermidine/spermine N1-acetyltransferase activity in the liver of lipopolysaccharide-treated mice. 150 19

In order to characterize the estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells and xenografts, their growth kinetic parameters and some biochemical characteristics concerning the receptor status and polyamine metabolism were determined and compared. The doubling times calculated from the growth curves showed higher proliferation rate of MDA-MB-231 cells, both in culture (21 hours) and in xenograft (9.7 days), in comparison to the MCF-7 cells which had values of 32 hours and 11.6 days, respectively. Growth-dependent changes observed in the intracellular putrescine, spermidine and spermine concentrations indicated a higher activity of polyamine metabolism in the MDA-MB-231 cells and xenograft as well. However, biosynthetic key-enzyme ornithine decarboxylase activity (ODC, EC 4.1.1.17) showed neither characteristic differences between the two types of breast cancer, nor consistent relationship with their proliferation rate. Metabolic alterations of the MCF-7 and MDA-MB-231 cell lines grown in vitro were also reflected in the polyamine composition of their culture medium. Independently of their receptor status, both types of breast cancer were responsive to difluoromethylornithine (DFMO) treatment. DFMO inhibited the ODC activity totally and depleted the cellular polyamine levels. MCF-7 cells in culture were more sensitive to the antitumoral effect of DFMO than the MDA-MB-231 line, while the rate of growth inhibition did not differ significantly in the xenografts. The present results provided further evidence on the different polyamine metabolism of ER-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells in vitro and in vivo, suggesting a correlation of hormonal modulation with polyamines as a determinant group of biological response modifiers.
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PMID:Comparative studies on the polyamine metabolism and DFMO treatment of MCF-7 and MDA-MB-231 breast cancer cell lines and xenografts. 176 53

Diverse data link estrogen influences to both the frequency and severity of systemic lupus erythematosus in humans and to murine lupus. A fundamental mechanism of action of estrogen involves the interaction of the hormone with its receptor protein, which is then transformed into the DNA binding form. We measured the concentration of uterine estrogen receptor and its DNA binding in normal BALB/c mice, lupus-prone MRL-lpr/lpr mice, and MRL-lpr/lpr mice that had been treated with 1% difluoromethylornithine (DFMO). Uterine estrogen receptor levels in 20-week-old mice from the 3 groups were not significantly different. In contrast, DNA binding activity was significantly higher in BALB/c mice (mean +/- SD 775 +/- 100 fmoles/mg of DNA) than in untreated MRL-lpr/lpr mice (80 +/- 16 fmoles/mg of DNA) (P less than 0.001). Treatment with 1% DFMO was associated with an increase in uterine estrogen receptor DNA binding (1,100 +/- 218 fmoles/mg of DNA) in MRL-lpr/lpr mice (P less than 0.001). Polyamine levels were 2-6-fold higher in the uterine tissues of untreated MRL-lpr/lpr mice compared with the BALB/c mice and were significantly reduced by DFMO treatment. Our results link uterine polyamine production to a dysfunction of the estrogen receptors in MRL-lpr/lpr mice. Reduction of the polyamine level by the irreversible inhibition of ornithine decarboxylase with DFMO restores estrogen receptor function.
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PMID:Restoration of the DNA binding activity of estrogen receptor in MRL-lpr/lpr mice by a polyamine biosynthesis inhibitor. 198 79

Studies on structurally related aromatic amines with different carcinogenic properties have shown that 2-acetylaminofluorene (2-AAF) and 2-acetylaminophenanthrene (AAP) inhibit the binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to the Ah receptor in vitro. The apparent inhibitor constants (Ki) are 2.3 microM for 2-AAF and 2.7 microM for AAP. In contrast, 4-acetylaminofluorene, an isomer of 2-AAF, and trans-4-acetylaminostilbene do not bind to the rat hepatic cytosolic Ah receptor. Pretreating female Wistar rats with 2-AAF or AAP leads to the induction of the P-450 isoenzymes that are under the control of the Ah receptor. Ornithine decarboxylase activity is induced by all aromatic amines tested irrespective of their Ah receptor affinity. The aromatic amines used as model compounds do not inhibit the binding of 17-beta-estradiol to the 8S and 4S estrogen receptor of rat uterus or rat liver in a competition assay analyzed using sucrose density gradient centrifugation. On the other hand, the aromatic amines bind to varying extents to another estrogen-binding protein of rat liver whose function and identity is still unknown. Our study demonstrates that structurally related aromatic amines in their unmetabolized form interact differentially with a cellular target protein, the Ah receptor, in vitro as well as in vivo. However, a relationship between these effects and the postulated promoting properties of 2-AAF remains to be established.
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PMID:Binding of aromatic amines to the rat hepatic Ah receptor in vitro and in vivo and to the 8S and 4S estrogen receptor of rat uterus and rat liver. 217 74

Estrogen and androgen receptors within the liver have been reported to modulate the hepatic regenerative response to partial hepatectomy. Moreover, cyclosporine has several untoward effects that might occur as a consequence of alterations in sex hormone activity. To evaluate these questions the following experiments were performed. Estrogen and androgen receptors in cytosol were quantitated in livers of rats treated with cyclosporine or olive oil vehicle before and after partial hepatectomy or a sham operation. Ornithine decarboxylase activity and thymidine kinase activity were assessed as indices of hepatic regeneration. Preoperative levels of estrogen receptor activity in the hepatic cytosol were significantly greater in rats treated with cyclosporine as compared to vehicle treated controls (P less than 0.01). In contrast, preoperative levels of androgen receptor activity in the cyclosporine-treated and vehicle-treated animals were similar. Following partial hepatectomy, a reduction in the activity of both sex hormone receptors in the hepatic cytosol was observed and was compatible with results described previously in normal animals. Unexpectedly the preoperative levels of ornithine decarboxylase (P less than 0.01) and thymidine kinase activity (P less than 0.01) were significantly greater in the rats treated with cyclosporine as compared to the vehicle treated controls. As expected, ornithine decarboxylase activity (at 6 hr) and thymidine kinase activity (at 24 hr) rose and peaked in response to a partial hepatectomy but were significantly greater (P less than 0.05) in the rats treated with cyclosporine as compared to the vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of cyclosporine on hepatic cytosolic estrogen and androgen receptor levels before and after partial hepatectomy. 229 96

A number of mechanisms participate in the hepatic injury that occurs during and following liver transplantation. A normal allograft regenerative response is probably essential for a successful transplant outcome. In this study, the effect of cyclosporine, a potent immunosuppressant used routinely after liver transplantation, on the regenerative response of the liver after partial hepatectomy was investigated. Male Wistar rats were pretreated for one week with either cyclosporine or the olive oil vehicle and were subjected to either a two-thirds partial hepatectomy or a sham operation. Animals were sacrificed at various times postoperatively and the remnant livers were weighed to determine the liver weight to body weight ratio, two biochemical measures of a regenerative response (cytosolic ornithine decarboxylase activity and thymidine kinase activity), and the hepatic content of estrogen and androgen receptors, as the content of these receptors has been shown to modulate, at least in part, the subsequent hepatic regenerative response. The preoperative hepatic cytosol content of ornithine decarboxylase, thymidine kinase, and estrogen receptor was significantly greater (P less than 0.05) in rats pretreated with cyclosporine than in those treated with the vehicle alone. A significant increase in ornithine decarboxylase and thymidine kinase activities occurred after partial hepatectomy in both the cyclosporine-pretreated and vehicle-pretreated animals. The absolute levels for each parameter were also greater in the cyclosporine-treated animals than in the vehicle-treated controls at 24 hr after partial hepatectomy (P less than 0.05). The pattern of change in the hepatic cytosolic content of estrogen and androgen receptors in both groups of animals was comparable with those described previously for regenerating liver.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclosporine augments hepatic regenerative response in rats. 230 86

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy.
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PMID:Effect of antiandrogen flutamide on measures of hepatic regeneration in rats. 259 58

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per se determines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli.
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PMID:Effect of tamoxifen on hepatic regeneration in male rats. 291 Jun 79

Although polyamines are important in regulating proliferation of mammalian cells, their role in hormone induction of cell growth has not been delineated. In the estradiol-responsive human breast cancer cell line, T-47D clone 11, estradiol (10(-10) M) was able to stimulate cell proliferation and the activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines. alpha-Difluoromethylornithine (DFMO), a specific inhibitor of ODC, blocked the estradiol-induced cell proliferation and ODC activity. Exogenous addition of putrescine, the natural product of ODC, rescued the inhibitory effect of DFMO. In addition, DFMO abolished the estradiol-induced growth of several other estrogen-responsive human breast cancer cell lines but did not affect the growth of hormone-independent cell lines. Further, a serum factor was found to be required for estradiol to exert its effect. To gain insight into the nature of this and possibly other extrinsic factors involved, the effect of estradiol on the proliferation of T-47D cells transplanted into athymic nude mouse was evaluated. In this in vivo system, estradiol alone produced only moderate growth of the human breast tumor. The simultaneous transplantation of a prolactin (PRL)- and growth hormone (GH)-secreting rat pituitary tumor or normal rat pituitary glands at a different site dramatically potentiated the effect of estradiol on the growth of the breast tumor xenograft. Purified PRL or GH were without effect, indicating that the active pituitary factor is neither PRL nor GH. Further, conditioned medium from rat pituitary tumor cells potentiated the mitogenic effect of estradiol on T-47D and several other estrogen receptor-positive human breast cancer cell lines in vitro under serum-free condition. In conclusion, we have identified both intrinsic (polyamines) and extrinsic (pituitary/serum) factors that are importance for estrogen to exert its mitogenic action. The next goal will be to elucidate the mechanisms of action of these molecules in the modulation of estrogen action.
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PMID:Intrinsic and extrinsic factors in estrogen action in human breast cancer: role of polyamines and pituitary factors. 308 72

The present studies were undertaken to determine the importance of the polyamine biosynthetic pathway in cellular proliferation and hormone-regulated progesterone receptor synthesis in estrogen receptor-containing breast cancer cells. Treatment of MCF-7 cells with difluoromethylornithine (DFMO), the irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), prevented estradiol-induced cell proliferation in a dose-dependent fashion. DFMO inhibition of estradiol-induced cell proliferation was completely recoverable by the addition of exogenous putrescine while putrescine alone did not stimulate proliferation of control cells. ODC activity was 4-fold greater in estrogen-treated cells and DFMO (5 mM) fully inhibited ODC activity. DFMO was able to suppress only slightly further the proliferation of antiestrogen (tamoxifen) treated cells and putrescine was able to recover this DFMO inhibition. In contrast to the suppressive effect of DFMO on cell proliferation, DFMO had no effect on the ability of estrogen to stimulate increased (4-fold elevated) levels of progesterone receptor. Hence, while ODC activity appears important for estrogen-induced cell proliferation, inhibition of the activity of this enzyme has no effect on the ability of estradiol to increase cellular progesterone receptor content.
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PMID:An evaluation of the involvement of polyamines in modulating MCF-7 human breast cancer cell proliferation and progesterone receptor levels by estrogen and antiestrogen. 311 62


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