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)

Liver carcinogenesis was induced in rats by aflatoxin B1 (AFB1) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), was administered by gavage to one group only during AFB1 administration; another group received DFMO during AFB1 administration and for 2 months after carcinogen administration. These two groups were compared to two control groups, one given AFB1 and fed the choline-deficient diet and another fed the deficient diet only. In a second experiment, DFMO was administered at a concentration of 2% in the water for 3 weeks and then at 1% for the remainder of the study. Rats from each group in Experiment 1 were killed at 2, 8, and 10 months after AFB1 administration and the development of tumors was followed by histology; autoradiography of [3H]thymidine incorporation into DNA; enzyme histochemistry; and alpha-fetoprotein determination. The group given DFMO during AFB1 administration was not significantly different from the AFB1-treated control group at 2 and 8 months after AFB1 administration. However, at 10 months following AFB1 and DFMO administration, the [3H]thymidine-labeling index and glucose-6-phosphatase staining were significantly increased. This group had three animals bearing hepatocellular carcinomas as compared to none in the controls. The group given DFMO for 2 months after AFB1 administration had a significantly depressed growth rate 2 months later, but this difference was not apparent after 8 months. After 10 months, there was a significantly increased [3H] thymidine-labeling index and increased volume fraction of gamma-glutamyltranspeptidase in the AFB1-DFMO-treated group as compared to the controls. DFMO appeared to inhibit growth under some conditions, but if administration was discontinued after AFB1 exposure, it appeared to enhance tumorigenesis. In Experiment 2, where a larger dose of AFB1 was used and DFMO was administered in the water from start to finish of the experiment, DFMO inhibited tumor induction and depressed the appearance of markers examined during carcinogenesis. These data indicate that the regimen used for DFMO administration can markedly affect tumor induction.
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PMID:Effects of the irreversible ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, aflatoxin B1, and choline deficiency on hepatocarcinogenesis. 241 77

The development of chemically induced hepatocellular carcinoma in the rat proceeds through a series of premalignant changes that may ultimately progress to a primary malignant tumor. Using the selection technique based on diminished binding of preneoplastic hepatocytes to tissue culture plates precoated with asialofetuin, we have isolated poly(A+)RNA from early preneoplastic foci as well as preneoplastic persistent nodules and primary hepatocellular carcinoma induced by the Solt-Farber protocol in the Fischer rat. The steady-state poly(A+)RNA levels of genes traditionally associated with growth, differentiation and/or transformation were then determined to address the question of their temporal expression in the multistep nature of cancer development. Ornithine decarboxylase- and P53-specific transcripts did not significantly change in preneoplastic foci but were increased in later-stage preneoplastic nodules and hepatocellular carcinoma. Albumin-specific transcripts were decreased in all hepatocellular carcinoma but there was no consistent coordinated increase in alpha-fetoprotein-specific transcripts. c-myc and raf transcripts increased at the very early preneoplastic foci stage and continued to increase throughout the neoplastic process. No L-myc or N-myc transcripts could be detected in any RNA sample. c-Ha-ras-specific transcripts were essentially unaltered in all RNA samples whereas no c-Ki-ras or N-ras transcripts could be detected throughout the neoplastic process. In addition, no dominant-acting transforming mutations in the ras gene family were detected by DNA transfection experiments using NIH/3T3 cells.
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PMID:Poly(A+)RNA levels of growth-, differentiation- and transformation-associated genes in the progressive development of hepatocellular carcinoma in the rat. 246 94

The synthetic estrogens, diethylstilbestrol (DES) and ethynylestradiol (EE2), are more potent than 17 beta-estradiol (E2) in inducing uterine weight gain in the neonatal rat, due to the binding of E2 to serum alpha-fetoprotein (AFP). However, all three hormones are equipotent in inducing neonatal uterine ornithine decarboxylase (ODC) activity. The present study assessed estrogen potency in fetal rats. Pregnant CD rats were injected sc daily on gestation days (GD) 16-20 with DES, EE2, or E2 in sesame oil. Both DES and EE2, but not E2, significantly increased uterine weight at birth, to more than twice that of controls. In addition, implants which continuously release E2 only slightly increased uterine weight at birth. Alternatively, dams were given a single estrogen injection on GD 20 and were sacrificed at various times after injection. Peak fetal uterine ODC activity occurred at 6-8 hours after maternal injection for all three estrogens. E2 had a relative potency about tenfold less than either DES or EE2 in stimulating fetal ODC activity, in contrast to equal potencies of the three estrogens in the postnatal rat uterus. Similar patterns were found following direct fetal injection with E2 or DES. In summary, these data demonstrate a transplacental induction of fetal uterine ODC activity and uterine weight gain by both DES and EE2. In addition, the lack of correlation between these endpoints in response to E2 suggests that they may be useful as selective indicators of potential toxicity of both natural and synthetic estrogens.
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PMID:Transplacental estrogen responses in the fetal rat: increased uterine weight and ornithine decarboxylase activity. 272 33

Specific transcriptional and translational products associated with regenerating liver were analyzed by differential hybridization to a cDNA library and by two-dimensional electrophoresis of hepatic proteins, respectively. Comparisons of approximately 800 soluble and 800 particulate liver proteins from normal and 70% partially hepatectomized Fischer rats resulted in the identification of only three apparently unique polypeptides in 70% partially hepatectomized livers, although many quantitative changes were observed. A subset of these quantitative changes were also observed after sham operation. A cDNA library was generated from polyadenylated RNA isolated 18 hr post-70% partial hepatectomy. Comparative analysis of 6,000 transformants with single-stranded cDNA probes prepared from 18 hr post-70% partial hepatectomy and sham-operated animals identified three clones whose sequences were preferentially expressed 4- to 6-fold 18 hr post-70% partial hepatectomy. Southern blot analysis of one clone, REG-A, showed no homology to albumin, alpha-fetoprotein, three different forms of cytochrome P-450, ornithine decarboxylase, globin, or to a putative tumor promotion associated gene called PRO-2. A single, REG-A specific 2.5 kb band was identified by Northern blot analysis of liver samples. REG-A expression was increased 2-fold 18 hr postsham operation; 4-fold 18 hr post-70% partial hepatectomy and following chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin or phenobarbital treatment. REG-A expression returned to control levels 1 week after 70% partial hepatectomy. Furthermore, expression of REG-A was reduced in chemically induced preneoplastic nodules and in primary and transplantable hepatomas. Hybrid selection studies indicated that the REG-A sequence selected a mRNA(s) species, that in an in vitro translation assay, produced two major polypeptides of 21,000 and 25,000 molecular weight with a pI of 6.9. Thus, these data support the hypothesis that liver regeneration is characterized by quantitative changes in genes normally expressed at low levels in the Go hepatocyte and is not the result of major qualitative changes in gene expression.
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PMID:Studies of gene transcription and translation in regenerating rat liver. 287 15

alpha-Difluoromethylornithine (DFMO), a highly selective inhibitor of ornithine decarboxylase (ODC), induced terminal differentiation of F9 mouse embryonal carcinoma cells in culture. Differentiation was assessed using morphological criteria and the level of plasminogen activator activity. The observed phenotypic changes and the fact that the cells did not synthesize alpha-fetoprotein, indicate that they were parietal endoderm cells. The putrescine, spermidine and spermine content of untreated control cells increased during exponential growth and then decreased gradually with continued time in culture. The increases in putrescine and spermidine contents were prevented by DFMO treatment. In fact, the putrescine and spermidine content decreased below the limits of detection after only one day of treatment. The addition of putrescine to the culture medium at any time within 4 days of DFMO treatment, prevented the DFMO-induced differentiation, suggesting that the effects observed were indeed caused by polyamine depletion. The phenotypic changes induced by DFMO were similar to those induced by retinoic acid, a very potent inducer of embryonal carcinoma differentiation. Although retinoic acid can inhibit ODC activity and putrescine accumulation, it is unlikely that this mechanism of action is responsible for retinoic acid-induced F9 cell differentiation, inasmuch as putrescine addition did not prevent the expression of the differentiated phenotype. Undifferentiated F9 embryonal carcinoma cells exhibited a very short G1 phase, and in this respect they are similar to the cells of the preimplantation mouse embryo. In control (exponentially growing) cultures a majority of the F9 cells were in the S phase, but in DFMO-treated cultures they accumulated in the G1 phase and showed no further proliferative potential.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of F9 embryonal carcinoma cell differentiation by inhibition of polyamine synthesis. 393 Feb 45

Suppression of serum alpha-fetoprotein (AFP) levels in glucocorticoid treated newborn rats was investigated. Daily intraperitoneal injection of 2 micrograms/g body weight of dexamethasone into newborn rats greatly reduced the concentration of AFP in the serum and liver cytosol. In contrast, this treatment stimulated liver ornithine decarboxylase activity. The reduction in AFP levels is not due to a change of distribution of AFP molecular variants, inhibition of secretion of synthesized AFP by the liver or disruption of liver polysomes. Glucocorticoids decrease the AFP levels in hormone-treated rats by supressing the synthesis of AFP. The size of AFP polysomes isolated from the livers of dexamethasone-treated rats were as large as those from normal rats. However, the amount of AFP-producing polysomes in hormone-treated rat liver is only 14% of the controls. By hybridization assays, it was found that dexamethasone treated livers contained decreased amounts of AFP mRNA sequences in liver cytoplasmic and nuclear RNAs. The decreased amounts of AFP mRNA sequences in hormone-treated liver are caused by both a decrease in the rate of AFP mRNA transcription and in AFP mRNA stability.
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PMID:Hormonal modulation of alpha-fetoprotein gene expression in newborn rat livers. 617 48

Fusarium sp. contaminated feedstuffs elicit adverse estrogenic effects in several commercially important animal species via the mycotoxin zearalenone. An estrogenically active synthetic derivative, zearalanol, is used as an anabolic agent in cattle. Since estrogens can irreversibly alter target tissue development, we investigated the estrogenic activity of these compounds in the neonatal rat uterus. Both induced dose-dependent premature uterine growth when injected daily on postnatal days 1-5 (ED50 = 1.3 mg/kg BW). Nuclear estrogen receptor levels dramatically increased 1 hour after either a single injection on day 5 or after five daily injections. In 5-day-old animals, the translocated nuclear receptor was characterized as a single class of binding sites with a dissociation constant (KD) for estradiol (E2) of 1 nM. At 15 days, zearalanol-treated animals showed greater uterine nuclear receptor retention than zearalenone-treated animals. In 5-day-old animals, single mycotoxin doses induced five fold elevations of ornithine decarboxylase (ODC) at 6 hours. Unlike the growth response, ODC dose-response studies showed zearalanol to be about 20-fold more effective than zearalenone. Time course studies revealed that a low dose of zearalenone, but not of zearalanol, resulted in a shift in peak activity from 6 to 8 hours. These data suggest that metabolism of zearalenone may be important in short-term pharmacodynamics. In a competitive binding assay, neither compound competed [3H]E2 from the E2 binding site on alpha-fetoprotein. We conclude that the uterine growth response and ODC induction demonstrate the neonatal estrogenic action of these mycotoxins, apparently mediated via the estrogen receptor. The greater effectiveness of zearalanol in inducing ODC may be related to nuclear retention and/or zearalenone metabolism.
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PMID:Estrogenic activity of zearalenone and zearalanol in the neonatal rat uterus. 623 18