Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intestinal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated in male and female Sprague-Dawley (SD) rats and male F344 rats, using isolated perfused intestinal segments. [1(-14)C]-NNK at 1 microM was metabolized by alpha-hydroxylation, pyridine N-oxidation and carbonyl reduction. Jejunal segments from control female rats metabolized 26.2% of the NNK during transepithelial transfer to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, 12.2%), 4-(methylnitrosamino)-1-3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide, 7.7%), 4-oxo-4-(3-pyridyl)-butanol (KAlc, 2.7%), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol (NNAL-N-oxide, 1.8%), 4-oxo-4-(3-pyridyl)butyric acid (KA, 1.1%) and 4-hydroxy-4-(3-pyridyl)butyric acid (HA, 0.7%). Ileal segments metabolized 20.8% of the NNK during absorption, with no difference in metabolite distribution as compared to jejunal segments. In control male SD and F344 rats, jejunal presystemic metabolism was 2.3-fold higher (56.4% and 60.8% respectively), mainly because of a 4-fold increase in NNAL formation (44.1% and 48.5%)> total NNK metabolism was also induced in female rats by starvation (84.4% metabolites), acetone (89.3%), phenobarbital PB, 75.3%) and Clophen A50 (61%). PB and Clophen A50 induced N-oxidation to 38.9% (4 x) and 27.8% (3 x), and to a lesser extent NNAL formation and alpha-hydroxylation (2 x), Starvation mainly increased N-oxidation with a time-dependent increase from 1 day to 3 days of starvation (4 x and 8 x versus controls), whereas alpha-hydroxylation and NNAL formation was elevated only after 1 day starvation. Acetone pretreatment (3 days) stimulated all three pathways (NNAL 2 x, N-oxidation 4 x, alpha-hydroxylation 4 x). In male F344 rats, starvation and acetone induced N-oxidation (5 x and 7 x) and alpha-hydroxylation (3 x and 5 x), and decreased NNAL formation by 40%, probably due to substrate competition or further metabolism of NNAL. In acetone-induced female SD rats, NNK metabolism was inhibited by in vivo pretreatment with phenethylisothiocyanate (PEITC) or in vitro addition of 1% ethanol to the perfusate. Both inhibition experiments reduced total metabolism by 20%; N-oxidation and alpha-dhyroxylation were reduced to values found in control rats, whereas NNAL formation increased from 31% to 51%.Inhibition of NNK metabolism by PEITC im male F344 rats was less pronounced compared to female SD rats; again a decrease in alpha-hydroxylation (6.7% to 3.3%) and N-oxidation (73.6% to 35.3) was accompanied by increased NNAL formation (9.8% to 41.0%).(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1995 Aug
PMID:Intestinal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats: Sex difference, inducibility and inhibition by phenethylisothiocyanate. 763 97

Colonic SCFA formation from fermentable carbohydrate is important for the maintenance of morphologic and functional integrity of the colonic epithelium. Carbohydrate-induced diarrhea occurs when the amount of carbohydrate entering the colon exceeds its fermentation capacity. Deficient availability or utilization of SCFA, mainly of n-butyrate, is the cause of diversion colitis and may play important roles in colonic carcinogenesis, in starvation and enterotoxigenic diarrhea, and in idiopathic UC.
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PMID:Colonic fermentation: metabolic and clinical implications. 786 76

Measurements of cell cycle phase fractions, particularly S-phase, are useful for studies of cell biology and carcinogenesis. Up-regulation of histone gene expression is tightly coupled to the G1-S-phase transition of the cell cycle, and mRNA levels rise 30-100-fold during S-phase. Labeling of histone H3 mRNA using in situ hybridization (ISH) was assessed as a measure of S-phase cells and compared with that found using in vivo 5-bromodeoxyuridine (BrdUrd) labeling in formalin-fixed rat colonic crypts under baseline, modified 72-h starvation, and 24-h refeeding conditions. The labeling index scored in single-labeled sections by histone H3 ISH tightly correlated with that found by in vivo BrdUrd labeling (r = 0.99, p < 0.0001) and clearly discriminated between the control, starved, and refed states (P < 0.001). In 180 crypt sections double labeled using histone H3 ISH and BrdUrd, 92% of 1572 labeled cells exhibited both nuclear BrdUrd and cytoplasmic histone H3 label. It is concluded that histone H3 ISH is an accurate measure of the S-phase fraction and provides an alternative to in vivo BrdUrd labeling in rat colon. This finding warrants validation in human studies.
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PMID:Histone H3 messenger RNA in situ hybridization correlates with in vivo bromodeoxyuridine labeling of S-phase cells in rat colonic epithelium. 856 47

We recently demonstrated the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rat intestinal segments, as well as the inducibility of intestinal NNK metabolism by starvation or acetone treatment. To improve our understanding of intestinal NNK turnover we have additionally investigated NNK metabolism in isolated perfused jejunal segments from NMRI mice and Syrian golden hamsters. [14C]NNK (1 micromol/l) was metabolized extensively by jejunal segments from female NMRI mice (88.5%) and female Syrian hamsters (86.4%), whereas in male NMRI mouse segments a slightly lower metabolism (68.8%) was observed. Alpha-Hydroxylation was the predominant metabolic pathway in mice (58% of total metabolism), whereas in female Syrian hamsters N-oxidation accounted for >50% of the metabolites [4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol 27%, 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone 22% of total radioactivity]. Formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was low in both species. Total NNK metabolism in male NMRI mice was increased by starvation to 84.4% and by acetone treatment to 90.0% of the absorbed radioactivity. This increase was due to an increase in N-oxidation, whereas the amounts of alpha-hydroxides and NNAL remained unchanged. In female Syrian hamsters acetone treatment had only minimal effects upon the metabolite composition. Acetone-treated NMRI mice and Syrian hamsters were additionally gavaged with the chemopreventive agent phenethylisothiocyanate (PEITC). In mice this treatment slightly decreased keto acid formation (0.6-fold, P<0.05), whereas in hamsters PEITC had no effect. In summary, intestinal metabolism of NNK in rats, mice and hamsters differs in both the extent of total metabolism (hamsters > or = mice > rats) and the metabolite composition, indicating major species differences.
Carcinogenesis 1996 May
PMID:Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by hamster, mouse and rat intestine: relevance of species differences. 864 Sep 18

p53 mutation is commonly associated with high-grade, high-stage human urothelial carcinomas. Recent studies suggest that p53 mutation in low-grade, low-stage bladder carcinomas may be correlated with the progression of the disease. In the present study, we used antisense RNA methodology in vitro to evaluate the significance of the loss of p53 function at an early stage of urinary bladder carcinogenesis. An immortalized nontumorigenic rat urothelial cell line (MYP3) that strongly expresses wild-type (WT) p53 was transfected with a plasmid (pcDL-SR alpha-296) containing a rat WT p53 cDNA in antisense orientation. The transfection resulted in a significant reduction in p53 mRNA expression and protein synthesis, in stimulation of anchorage-dependent growth, and in acquisition of anchorage-independent growth potential. Three such clones, when tested in athymic nude mice, all formed muscle-invasive, high-grade transitional cell carcinomas at s.c. injection sites. When cells were inoculated into an orthotopic site (urinary bladder), one of two antisense transfectants tested formed bulky tumors in the bladder in all seven nude mice and metastases to lungs in three of the seven mice. Analysis of these cells revealed a decrease in the expression of p21 (WAF1, sdi1, or CIP1) and retinoblastoma (Rb) gene product. Phosphorylation of Rb protein was not inhibited when the cells were starved. No significant difference was observed in the expression of p16 protein. In cell cycle analysis, all antisense transfectants tested escaped from G1 arrest by starvation. Furthermore, secretion of interleukin (IL)-6 into culture medium was increased significantly. Treatment with anti-IL-6 antibody suppressed anchorage-dependent growth. This study directly demonstrates that the loss of p53 function at an early stage of urothelial carcinogenesis may result in acquisition of a malignant phenotype by regulating IL-6 production as well as cell cycle related genes.
Carcinogenesis 1998 Jan
PMID:Antisense RNA-mediated reduction of p53 induces malignant phenotype in nontumorigenic rat urothelial cells. 947 96

The scope of the present study was to investigate whether nicotine or cotinine will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated perfused rat lungs and livers and to study the effect of starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK elimination and metabolism and led to a substantial increase of elimination half-life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after cotinine co-administration, respectively. In parallel, the pattern of NNK metabolites was changed by nicotine and cotinine. The pathway of alpha-hydroxylation representing the metabolic activation of NNK was decreased to 77% and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2-fold in presence of nicotine and cotinine, respectively. When isolated rat lungs were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of metabolites were substantially affected due to co-administration of 50 microM nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the activation of NNK and can be induced by starvation. However, isolated rat lungs from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 microM for 3 h, revealed only small differences in pulmonary elimination and pattern of NNK metabolites between fed and starved animals. These results suggest that nicotine and its main metabolite cotinine inhibit the metabolic activation of NNK predominantly in the liver whereas activation in lung, a main target organ of NNK induced carcinogenesis, remained almost unaffected.
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PMID:Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver. 955 Mar 8

We have previously described an inverse relationship between Cdx1 and Cdx2 mRNA levels and the extent of dysplasia and severity of clinical outcome in colorectal carcinoma, suggesting that altered expression of these genes was associated with colorectal carcinogenesis or tumor progression. To investigate further their involvement in the physiopathology of colorectal cancer, HT29 colon carcinoma cells that show very low Cdx expression were transfected with Cdx1 and/or Cdx2 cDNA to elicit their overexpression. Growth rate, tumorigenicity, resistance to apoptosis, and migration potential of the corresponding cells were analyzed. Growth rate of cells overexpressing Cdx2 decreased by half, whereas overexpression of Cdx1 had no effect. However, cells overexpressing both Cdxs had a growth rate reduced to 20% of control. In cells overexpressing Cdx1 or Cdx2, tumorigenicity and resistance to apoptosis induced by serum starvation, ceramide, or staurosporine were not changed compared with control cells; yet phorbol ester-stimulated cell migration was decreased by 50%. In cells overexpressing both Cdx1 and Cdx2, tumorigenicity was decreased by 50%, resistance to apoptosis was significantly lowered, and stimulated cell migration was further decreased to 15% of control compared with cells expressing Cdx1 or Cdx2. Finally, cells overexpressing both Cdxs showed strongly decreased Bcl-2 expression, which could account for their increased sensitivity to apoptosis. These findings show that, in HT29 cells, both Cdx1 and Cdx2 genes must be expressed to reduce tumorigenic potential, to increase sensitivity to apoptosis, and to reduce cell migration, suggesting that the two genes control the normal phenotype by independent pathways. This may explain why loss of Cdx1 or Cdx2 expression is associated with tumor development and invasiveness in colorectal tumors.
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PMID:Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. 959 54

A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.
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PMID:p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. 961 91

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been identified, the Raf protein kinases which are upstream regulators of the mitogen-activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic effectors. Constitutive upregulation of this pathway by oncogenic ras is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2 were not detectable under conditions of exponential growth or serum-starvation. Depending upon the cell line, the block in Erk signaling was observed to occur at either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack of Erk activation observed in both cell lines and primary tumor tissue suggests that constitutive Erk activation may not be required for tumor maintenance or progression in K-ras transformed pancreatic cells. We hypothesize that other Ras-dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have important implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.
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PMID:Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. 1040 37

With a previous paper (Niu & Wang, 1995), a general, hypothetical outline of the mechanism of carcinogenesis was proposed. With reference to the fact of starvation-induced hypermutation in micro-organisms, we propose that the hypoxia commonly seen in the cells at the centre of solid tumours might also result in hypermutation, and then p53-dependent programmed cell death. Like the apparently adaptive mutations in micro-organisms, only those genes (e.g. p53) that enable the cells to escape from apoptosis may be selected.
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PMID:Ideas in theoretical biology. Origin of cancerous cells from tumours. 1042 29


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