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)

The reduction of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-oxopropyl)propylamine (NOPPA) by hepatic and pancreatic cytosol and microsomes from Syrian golden hamsters and Sprague-Dawley rats has been examined. All hepatic fractions reduced both substrates, although the activity depended on the fraction tested and the cofactor employed (NADH or NADPH). Generally, hamster hepatic fractions contained higher activity than the rat hepatic fractions and BOP was a better substrate than NOPPA. Of the pancreatic fractions, only cytosol exhibited reductase activity. The hamster cytosol was able to utilise both cofactors, but the rat fraction exhibited activity only when NADPH was present. BOP was the better substrate for the pancreatic enzymes and in the presence of NADPH, the rat and hamster activities were about equal. These results suggest that the pancreatic reduction of BOP to HPOP is unlikely to be a significant factor in the species-specific induction of pancreatic cancer by BOP.
Carcinogenesis 1983 Nov
PMID:Enzymatic reduction of beta-ketonitrosamines. 664 Aug 48

The enzyme NADPH-cytochrome c (P-450) reductase was identified by indirect immunofluorescence in hepatocytes, bronchioles, and proximal tubules of liver, lung, and kidney, respectively, of rats and minipigs that had been injected with phenobarbital or saline. The distribution of this component of the cytochrome P-450-mediated microsomal system may be relevant to sites of drug toxicity and carcinogenesis.
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PMID:Immunofluorescence of NADPH-cytochrome c (P-450) reductase in rat and minipig tissues injected with phenobarbital. 677 Apr 64

Nitrite was formed on incubation of N-nitrosamines with a reconstituted monooxygenase system, consisting of cytochrome P-450 (P-450) and NADPH P-450 reductase from pig liver. Nitrite was not obtained when the nitrosamines were incubated with NADPH P-450 reductase alone or when molecular oxygen or NADPH were omitted. Interaction of nitrosamines with the reconstituted P-450 system or with hemoglobin under reducing conditions resulted in optical spectra identical with those obtained with nitrite. It is proposed that N-nitrosamines are denitrosated by electron transfer from the hemoprotein iron to the nitrosamine molecule.
Carcinogenesis 1982
PMID:Metabolic nitrite formation from N-nitrosamines: evidence for a cytochrome P-450 dependent reaction. 680 75

Most chemical carcinogens require activation by polysubstrate monooxygenase. The phosphorylation of essential components of this cytochrome P-450 monooxygenase system, isolated from rabbit liver microsomes, cytochrome P-450 (LM2) and cytochrome reductase, was tested using two different protein kinases. One of the kinases, a cyclic AMP-independent phosvitin kinase (kinase P), was inactive in all systems tested. However, the catalytic subunit of a cyclic AMP-dependent protein kinase (kinase C) catalyzed phosphoryl group transfer to both proteins, but to different extents. Cytochrome P-450 was phosphorylated when added as sole component and also when in the presence of P-450 reductase and phosphatidylcholine. In contrast, the weak phosphorylation of P-450 reductase was reduced considerably in a complete reconstituted system containing P-450 and phosphatidylcholine. The inclusion of kinase P did not alter these results which excludes the possibility that these kinases participate in a sequential phosphorylation mechanism. The monooxygenase constituents themselves were without kinase activity. When hepatic microsomes were isolated in presence of the phosphatase inhibitor sodium fluoride no significant change in monooxygenase (7-ethoxycoumarin O-deethylation) activity was observed, whilst after preincubation with either acid or alkaline phosphatase a significant reduction in monooxygenase activity was measured. Thus, cytochrome P-450 (LM2) is phosphorylatable by protein kinase C and the catalytic activity of polysubstrate monooxygenase decreases after preincubation of microsomes with phosphatases.
Carcinogenesis 1983
PMID:Phosphorylation of cytochrome-P-450-dependent monooxygenase components. 685 Sep 89

The N-nitroso-compounds and the bacteriological contamination of gastric juice could represent a risk factor for cancer of the stomach when the mucosal barrier is altered. In the unresected stomach and gastric stump, the hypo-achlorhydria and bilopancreatic reflux permit the development of bacterial flora and the production of N-nitroso-compounds in the presence of nitrite. A survey was performed on 71 patients: 15 normal controls, 31 with gastroduodenal disease (9 gastrites, 10 gastric ulcers, 10 duodenal ulcers, 7 neoplasias), 20 patients with gastric resection (8 BI, 12 BII), using an endoscopic-histopathologic control and a chemical-bacteriological analysis of the gastric juice. We studied the gastric juice for the following parameters: pH, concentration of nitrite, identification of bacterial type, count and nitrate-reductase activity. An inverse relationship was found between the concentration of nitrite and the hydrogen ion concentration. In the alkaline gastric juice, we identified aerobic bacteria with nitrate-reductase activity and anaerobic bacteria. The latter has the ability to transform biliary salts into carcinogenic and cocarcinogenic compounds and to catalyze the nitrosations. The chemicobacteriological characteristics of the gastric juice from gastric ulcers (Johnson type I), atrophic gastrites, and resected stomachs lead one to think that there is a risk of carcinogenesis brought about by the N-nitroso-compounds.
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PMID:Gastric juice nitrite and bacteria in gastroduodenal disease and resected stomach. 686 41

The nature of the denitrosation of nitrosamines by rat liver microsomes was investigated. The rates of NADPH-dependent nitrosamine demethylation and denitrosation were compared in the same incubation mixture using several types of microsomes and inhibitors. Pretreatment with isopropanol, pyrazole, phenobarbital, and 3-methylcholanthrene had parallel effects on the microsomal demethylation and denitrosation reactions. Nitrite was produced with N-nitrosodimethylamine, N-nitroso-N-methylethylamine, N-nitroso-N-methylbutylamine, N-nitroso-methylbenzylamine, or N-nitroso-N-methylaniline as a substrate. With control microsomes, the rate of the denitrosation reaction was 9-39% that of demethylation depending on the type and concentration of nitrosamines used. Using nitrosodimethylamine as the substrate, the Km of denitrosation was about twice that of the demethylation reaction. Several polar organic solvents such as ethanol and isopropanol inhibited the denitrosation and demethylation reactions and each solvent inhibited both reactions to about the same extent. In the presence of cumene hydroperoxide, microsomes can catalyze the denitrosation of nitrosodimethylaime which is also accompanied by demethylation. Studies with a reconstituted system and with inhibitors indicate that the denitrosation reaction requires the presence of both cytochrome P-450 and NADPH-cytochrome-P-450 reductase. The results suggest that the denitrosation is closely linked to the demethylation reaction.
Carcinogenesis 1982
PMID:The nature of nitrosamine denitrosation by rat liver microsomes. 713 59

Previous work has demonstrated that dehydroepiandrosterone (DHEA) strongly inhibits growth and de novo cholesterol (CH) biosynthesis in preneoplastic rat liver. Administration of a mixture of 4 ribo- or deoxyribonucleosides of adenine, guanine, cytosine and uracil/thymine, prevents growth inhibition but not inhibition of CH synthesis. The purpose of this paper was to identify the site of inhibition of CH synthesis by DHEA. Persistent nodules (PNs) were induced, in diethylnitrosamine-initiated male F344 rats, by 'resistant hepatocyte' protocol. Fifteen weeks after initiation, nodule bearing rats and normal controls received a diet containing 0.6% DHEA for 3 weeks. They were then killed. 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity and mRNA levels were 18- and 14-fold higher, respectively in nodules than in normal liver. DHEA strongly inhibited HMGR activity in both tissues in vivo, but had a slight effect on HMGR activity, when added in vitro to the reaction mixture for determination of this activity. In vivo DHEA treatment caused a 65% decrease in the level of HMGR mRNA in PNs, which, however, does not seem to completely account for the decrease in HMGR activity (83%). Low density lipoprotein receptor (LDL-R) mRNA level underwent a slight decrease in PNs, with respect to control liver, which did not lead to a significant decrease in 125I-LDL binding to LDL-R. DHEA treatment caused 30% and 24% increases in LDL-R expression and 125I-LDL binding, respectively, in nodules. These observations indicate that in addition to HMGR gene expression, increased influx of LDL into preneoplastic cells may contribute to the deregulation of mevalonate synthesis by DHEA. The observation that HMGR activity and gene expression were still 3- to 5-fold higher in PNs of DHEA-treated rats than in control liver, and previous findings of preneoplastic liver cell growth in the presence of relatively low CH synthesis, suggest that even relatively low levels of mevalonate are sufficient for the growth of preneoplastic liver cells.
Carcinogenesis 1995 Jul
PMID:Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase activity and gene expression by dehydroepiandrosterone in preneoplastic liver nodules. 761 86

Certain enzymes of the mevalonate pathway have been investigated in persistent liver nodules induced in the rat by 2-acetylaminofluorene. In these nodules the dolichol level was increased 5-fold, the ubiquinone-9 content elevated 6-fold and the amount of cholesterol unchanged. Microsomal beta-hydroxy-beta-methylglutaryl-coenzyme A reductase activity was greatly increased compared to control liver tissue, which was also the case for the cytosolic farnesyl pyrophosphate synthase. A significant elevation of all-transgeranylgeranyl pyrophosphate synthase activity in the cytosol was also observed. The branch-point enzyme of microsomal dolichol synthesis, i.e. cis-prenyltransferase, was decreased in the nodules; whereas the activity of squalene synthase, the terminal regulating enzyme of cholesterol synthesis, remained unchanged. The dolichol species in nodular tissue were redistributed towards the longer chain length species. One factor regulating the chain length of the polyisoprene products formed in vitro was shown to be the ratio of the concentrations of isopentenyl pyrophosphate:farnesyl pyrophosphate employed. Other regulatory factors in the terminal steps of this biosynthetic pathway appear to determine the amounts and nature of the final isoprenoid compounds formed in vivo. In contrast to the microsomal trans-prenyltransferase activity, which was unchanged, the activity of nonaprenyl-4-hydroxybenzoate transferase, an enzyme participating in ubiquinone synthesis, was greatly elevated. The alterations observed in the activities of enzymes in the mevalonate pathway can at least partially explain the increased levels of dolichol and ubiquinone and the unchanged level of cholesterol found in liver nodules. It is reasonable to propose that this modified mevalonate metabolism will render nodular cells resistant to certain toxic factors and prone to cell proliferation.
Carcinogenesis 1995 Mar
PMID:Enzymes of the mevalonate pathway in rat liver nodules induced by 2-acetylaminofluorene treatment. 769 19

Cholesterol is widely distributed in the animal kingdom and occurs in all cell membranes. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, all cells in the body have genomic information for cholesterol biosynthesis. Cholesterol biosynthesis is under feedback regulation, and the cellular and circulating cholesterol levels are tightly regulated at several points, such as the rate limiting enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and farnesyl pyrophosphate synthetase and at the low density lipoprotein (LDL) receptor. The cholesterol content and the rate of cholesterol biosynthesis are elevated in proliferating normal tissues and tumors. Cholesterol biosynthesis happens much before DNA synthesis, and inhibiting cholesterol biosynthesis inhibits cell growth, suggesting a linkage between the cholesterol and DNA synthetic pathways. The exact nature of this linkage is not known. However, recent evidence that the farnesyl moiety in the cholesterol biosynthetic pathway is necessary for the activation of G-proteins, and of the ras oncoprotein P21 has provided a probable basis for understanding this linkage, through signal transduction pathways. Thus, farnesylation of G proteins and ras oncoprotein P21 underscores the importance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis. During normal cell growth and differentiation, LDL acts as a negative growth regulator and growth factors as positive signals, the neoplastic cell achieving autocrine growth due to the activation of protooncogens. It is interesting to note that in several types of cancer, the ras gene is mutated; these mutations could increase GTP binding, and lead to an activated p21. The activation of p21 would then be aided by continuous farnesylation due to stimulation of the cholesterol biosynthetic pathway in tumors. The cholesterol biosynthetic pathway, and ras p21 could therefore be used as targets for chemoprevention of cancer.
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PMID:The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis (review). 776 99

Sex differentiation of liver functions has been shown to be attenuated in preneoplastic rat liver nodules. The present study was performed to investigate whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions. Male and female Wistar rats were treated according to a modified resistant hepatocyte model (RH-model), with diethylnitrosamine initiation and promotion with intragastric administration of 2-acetylaminofluorene (2-AAF) combined with partial hepatectomy (PH). Eleven months post-initiation male rats were treated with either human (hGH) or bovine growth hormone (bGH) or ovine prolactin (oPRL) by continuous infusion for 1 week. The mRNA expression of a number of genes known to be sex differentiated in liver from adult control rats was compared in nodular and surrounding tissue from nodule-bearing male, female and hormone-treated male rats. The basal mRNA expression of the female-predominant cytochrome P4502C12 (CYP2C12) was increased and the male-predominant CYP2C11 was decreased in liver nodules from male rats compared with the surrounding liver. Expression of the prolactin receptor (PRL-r; female > male) and the steroid 5 alpha-reductase (female > male) genes was decreased in male nodules, whereas no difference was observed with respect to GH-receptor (GH-r; female > male) expression in nodules versus surrounding tissue. Early nodules obtained from males treated according to the original RH-model (dietary 2-AAF, 0.02%) and isolated 2 weeks after completion of the 2-AAF/PH treatment showed significantly lower GH-r mRNA levels than the total liver tissue. In hepatocellular carcinomas from hormonally unmanipulated males 11 months post-initiation the decrease in PRL-r expression was even more pronounced than in the nodules and a significant decrease in GH-r expression was seen. In female nodules the only significant difference with respect to the sex differentiated parameters was a lower 5 alpha-reductase expression than in the surrounding tissue. Continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue. oPRL also eliminated the differences between nodules and surrounding tissue in males and partly feminized the expression of both the 5 alpha-reductase and the PRL-r genes.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1995 Feb
PMID:Hormonal regulation of sex differentiated parameters in liver nodules from rats treated in the resistant hepatocyte model. 785 53


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