Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor tissue sampled from 88 patients with carcinoma of the corpus uteri was compared with the ostensibly normal tissue of the endometrium taken from 21 cases of uterine fibromyoma. The levels of malonic dialdehyde--a by-product of lipids peroxidation (LP)--in tumor tissue was slightly lower at basal conditions, and higher than in normal endometrium, following in vitro stimulation with ascorbates and, especially, NADP. An average LP rate in endometrial tumor (stage II-III) tissue was higher than in cases of stage I tumor. However, a direct correlation was observed between LP rates and estrogen and progesterone receptor levels in tumor tissue, while the former depended on the degree of tumor invasion little, if at all. It is suggested that LP rate variation in endometrial carcinoma tissue may be due to a spectrum of causes. Some of them may be associated with an accelerated and, possibly, highly pernicious course of the disease, while the others--with free radicals reactions being involved in hormonal carcinogenesis mechanisms.
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PMID:[Lipid peroxidation in endometrial cancer tissue: connection with hormonal sensitivity and hormonal cancerogenesis]. 880 39

The putative anticarcinogenic activity of Brassica vegetables has been associated with the presence of certain glucosinolates. 4-Methylsulphinylbutyl isothiocyanate (sulphoraphane), derived from the corresponding glucosinolate found in broccoli, has previously been identified as a potent inducer of the anticarcinogenic marker enzyme quinone reductase [NADP(H):quinone-acceptor oxidoreductase] in murine hepatoma Hepa 1c1c7 cells. We have therefore produced a broccoli hybrid with increased levels of this anticarcinogenic glucosinolate and tested the ability of extracts to induce quinone reductase. A 10-fold increase in the level of 4-methylsulphinylbutyl glucosinolate was obtained by crossing broccoli cultivars with selected wild taxa of the Brassica oleracea (chromosome number, n = 9) complex. Tissue from these hybrids exhibited a >100-fold increase in the ability to induce quinone reductase in Hepa 1c1c7 cells over broccoli cultivars, due to both an increase in 4-methylsulphinylbutyl glucosinolate content and increased percentage conversion to sulphoraphane.
Carcinogenesis 1998 Apr
PMID:Selective increase of the potential anticarcinogen 4-methylsulphinylbutyl glucosinolate in broccoli. 960 Mar 44

Cancer chemoprevention is inhibition of neoplastic disease by naturally occurring or synthetic chemical agents. Dithiolethiones inhibit production of experimentally produced tumors by elevating the expression of several genes that encode for known cytoprotective enzymes. In an effort to discover additional molecular mechanisms mediating chemoprevention, cDNA clones representing a gene that is transcriptionally activated by dithiolethiones, hence named dithiolethione-inducible gene-1 (DIG-1), were isolated from rat liver via differential hybridization screening. The deduced amino acid sequence of DIG-1 was found to have 80% identity with the human liver enzyme leukotriene B4 (LTB4) 12-hydroxydehydrogenase. DIG-1, purified >400-fold from the liver of rats dosed with 1,2-dithiole-3-dithiolethione, possessed an NADP+-dependent activity to convert LTB4 to 12-oxo-LTB4. Kinetic analysis of DIG-1 revealed apparent Km and Vmax values of 28 mM and 8.1 nmol 12-oxo-LTB4 formed/min/mg purified protein respectively. Since LTB4 is a potent chemotactic factor and stimulator of production of reactive oxygen species from neutrophils, the effects of DIG-1 on these LTB4-mediated processes were examined. Pre-incubation of LTB4 with purified rat hepatic DIG-1 greatly diminished LTB4-stimulated migration of neutrophils. In addition, pre-incubation of LTB4 with purified rat hepatic DIG-1 reduced LTB4-stimulated production of superoxide anions in neutrophils, as evidenced by decreased lucigenin-derived chemiluminescence. These results suggest that DIG-1-catalyzed dehydrogenation of LTB4 to 12-oxo-LTB4 inhibits the pro-inflammatory actions of LTB4. Consequently, elevation of LTB4 catabolism via enhanced DIG-1 activity may suppress inflammatory processes implicated in tumorigenesis.
Carcinogenesis 1998 Jun
PMID:Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention. 966 37

Carbonyl reductase (secondary-alcohol:NADP(+) oxidoreductase, EC 1.1. 1.184) belongs to the family of short chain dehydrogenases/reductases (SDR). Carbonyl reductases (CBRs) are NADPH-dependent, mostly monomeric, cytosolic enzymes with broad substrate specificity for many endogenous and xenobiotic carbonyl compounds. They catalyze the reduction of endogenous prostaglandins, steroids, and other aliphatic aldehydes and ketones. They also reduce a wide variety of xenobiotic quinones derived from polycyclic aromatic hydrocarbons. CBR reduces the anthracycline anticancer drugs, daunorubicin(dn) and doxorubicin (dox) to their C-13 hydroxy metabolites, changing the pharmacological properties of these drugs. Emerging data on CBRs over the last several years is generating new insights on the potential involvement of CBRs in a variety of cellular and molecular reactions associated with drug metabolism, detoxication, drug resistance, mutagenesis, and carcinogenesis.
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PMID:Carbonyl reductase. 1115 33

An examination has been made of some of the parameters which can affect mutant numbers in the Salmonella/microsome assay. The type of minimal media plates used for the assay and the concentration of glucose-6-phosphate, one of the co-factors necessary for mono-oxygenase action, had no effect on mutant numbers. Increases in mutated bacteria resulted from the use of (1) log-phase bacteria, (2) higher NADP concentrations than those normally recommended, and (3) higher phosphate buffer concentrations. Six mutagens, i.e., 2-acetylaminofluorene (AAF), 3,3'-dichlorobenzidine (3,3'-DCB), cyclophosphamide (CY), aflatoxin B1 (AFB1), 3-methylcholanthrene (3MC) and benzo[a]pyrene (BP), all requiring mono-oxygenase activation, were studied with two Salmonella typhimurium strains, TA98 and TA100, and liver preparations from rats given different inducing agent treatments using optimum conditions. Phenobarbitone induction was generally superior to Aroclor-1254 in converting these substrates to mutagens except for the polycyclic hydrocarbon substrates. A comparison of 3-methylcholanthrene, Aroclor-1254, beta-naphthoflavone or phenobarbitone as inducing agents revealed the first three of these to be equally effective in activating BP or 3MC to mutagens, whereas phenobarbitone was less active. Dual administration of 3-methylcholanthrene and phenobarbitone to rats did not result in an additive mutagenic effect using AAF, AFB1 or 3,3'-DCB as substrates, the numbers of mutant bacteria obtained being only equal to that seen with 3-methylcholanthrene alone. These differences were not due to there being different liver protein optima for the various inducing agent treatments. The foregoing results are discussed in relation to attempts to draw up a rigid protocol for mutagenicity testing.
Carcinogenesis 1980
PMID:Some factors affecting mutant numbers in the Salmonella/microsome assay. 1121 44

The pyruvate kinase isoenzyme M2-PK is known to be associated with a metabolic shift that is characteristic for tumor cells. Meanwhile, the universal expression of this isoenzyme is the basis for the detection of various tumor diseases in human clinical diagnosis. Other enzymes which are known to be essential for this tumor specific metabolic shift in rat chemical carcinogenesis are the NADP-dependent enzymes malic enzyme, isocitrate dehydrogenase and glucose 6-phosphate dehydrogenase. To evaluate the role of these enzymes in human carcinogenesis, we compared their enzymatic activities in normal colon mucosa and tissues derived from primary colon tumors. Histochemical staining showed that the enzyme activities were restricted to mucosal colon cells and colon cancer cells. The enzymes were strongly but heterogeneously expressed in the tumor tissues, whereas staining of normal mucosa was weak. Tumor M2-PK showed the most prominent differences in normal colon mucosa and colon cancer cells.
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PMID:Tumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells. 1132 87

Biochemical and clinical evidence indicates that monomethylated selenium compounds are crucial for the tumor preventive effects of the trace element selenium and that methylselenol (CH(3)SeH) is a key metabolite. As suggested by Ganther (Ganther, H. E. (1999) Carcinogenesis 20, 1657-1666), methylselenol and its precursor methylseleninate might exert their effects by inhibition of the selenoenzyme thioredoxin reductase via the irreversible formation of a diselenide bridge. Here we report that methylseleninate does not act as an inhibitor of mammalian thioredoxin reductase but is in fact an excellent substrate (K(m) of 18 microm, k(cat) of 23 s(-1)), which is reduced by the enzyme according to the equation 2 NADPH + 2 H(+) + CH(3)SeO(2)H --> 2 NADP(+) + 2 H(2)O + CH(3)SeH. The selenium-containing product of this reaction was identified by mass spectrometry. Nascent methylselenol was found to efficiently reduce both H(2)O(2) and glutathione disulfide. The implications of these findings for the antitumor activity of selenium are discussed. Methylseleninate was a poor substrate not only for human glutathione reductase but also for the non-selenium thioredoxin reductases enzymes from Drosophila melanogaster and Plasmodium falciparum. This suggests that the catalytic selenocysteine residue of mammalian thioredoxin reductase is essential for methylseleninate reduction.
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PMID:Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium. 1178 68

A study of the morphological structure and functional activity of the rat thyroid gland was carried out after 22 months following a single exposure to external radiation. The 3-month-old animals were irradiated with doses of 0.25, 0.5, 1.0, 2.0 and 5.0 Gy. Blood was assayed for thyroxin (T4) and triiodothyronine (T3) levels, while liver tissue--for NADP-MDH activity and thyroid tissue--for thyroperoxidase activity. The thyroid was studied histologically, morphometrically and by electron microscope. The decreased T4 concentrations 2.59-fold in the 5.0 Gy group, the increased T3/T4 in the 2.0 and 0.25 Gy groups, the reduced diameter of cellular nuclei and follicles, the flat follicular epithelium and diminished number of thyrocyte ultrastructures indicate thyroid hypofunction in the irradiated animals. The morphological changes are characterized by enhanced diffuse and focal sclerotic changes in thyroid, most pronounced at high irradiation doses (1.0-5.0 Gy), whereas the hemosiderosis foci suggest that the structural changes are consequences of radiation-induced destructive injuries in the gland parenchyma. Two of the thyroids (0.5 Gy) demonstrate foci with pronounced lymphoid infiltration, while follicular carcinomas were detected in 4 thyroids (2.0 Gy), and in one thyroid (0.5 Gy) in one thyroid (5.0 Gy). The remote effects of radiation were dose-dependent destructive, sclerotic and atrophic processes, decreased functional activity, stimulation of development of autoimmune aggression and carcinogenesis in thyroid.
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PMID:[Functional and morphological characterization of rat thyroid gland at remote periods following single high and low dose radiation exposure]. 1557 Oct 41

Aldo-keto reductases (AKRs) are soluble NAD(P)(H) oxidoreductases that primarily reduce aldehydes and ketones to primary and secondary alcohols, respectively. The ten known human AKR enzymes can turnover a vast range of substrates, including drugs, carcinogens, and reactive aldehydes. They play central roles in the metabolism of these agents, and this can lead to either their bioactivation or detoxication. AKRs are Phase I drug metabolizing enzymes for a variety of carbonyl-containing drugs and are implicated in cancer chemotherapeutic drug resistance. They are involved in tobacco-carcinogenesis because they activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active o-quinones, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. They also detoxify reactive aldehydes formed from exogenous toxicants, e.g., aflatoxin, endogenous toxicants, and those formed from the breakdown of lipid peroxides. AKRs are stress-regulated genes and play a central role in the cellular response to osmotic, electrophilic, and oxidative stress.
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PMID:Aldo-keto reductases and bioactivation/detoxication. 1697 May 45

NADP(H):quinone oxidoreductase 1 (NQO1) and microsomal epoxide hydrolase (EPHX1, also mEH) are attractive candidate enzymes for association with colorectal neoplasia because they metabolize a number of compounds including polycyclic aromatic hydrocarbons (PAHs) that have been linked with colorectal carcinogenesis. We examined the relationship between NQO1C609T, mEH3, mEH4 and risk of sporadic distal colorectal adenomas in one of the largest case-control studies of 946 polyp-free controls and 894 cases, all participants of the UK Flexible Sigmoidoscopy Screening (UKFSS) Trial. The polymorphisms were examined as independent risk factors and evidence for interaction with smoking and alcoholic drinks was sought. The NQO1 609*T allele was positively associated with high-risk adenoma in this population [odds ratio (OR), 1.36; 95% confidence interval (CI), 1.02-1.83]. Elevated risk estimates were seen in smokers independently of the genotype but the association was stronger among current smokers with the heterozygous variant genotype (OR, 4.24; 95% CI, 2.54-7.09). It was reported for the first time that the association between alcohol and colorectal adenoma was modified by NQO1C609T genotype, such that the relation between alcohol and colorectal adenoma was stronger among those with the common C/C genotype (OR, 1.49; 95% CI, 1.11-2.02; P-interaction = 0.024). There was no association between mEH3 and mEH4 variants and colorectal adenoma risk and no effect modification by alcohol and smoking. These findings provide evidence for an important role of the NQO1C609T polymorphism in susceptibility of colorectal adenomas. Alcohol increases risk of colorectal adenoma in carriers of the high-activity genotype possibly through enhanced activation of alcohol-related procarcinogens.
Carcinogenesis 2007 Apr
PMID:Role of NQO1C609T and EPHX1 gene polymorphisms in the association of smoking and alcohol with sporadic distal colorectal adenomas: results from the UKFSS Study. 1708 76


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