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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The time course of changes in a number of biochemical parameters in rat liver was studied during 10 days of clofibrate administration. Ornithine decarboxylase (ODC) and putrescine levels began to increase within hours of the first dose and reached maxima at about 36 h (40 and 10 times control levels, respectively) and then returned to normal levels by 48 h. This ODC induction by clofibrate is different from that seen in compensatory liver hyperplasia or diethylnitrosamine administration in that it was not accompanied by elevations in cAMP or increased activation of cytoplasmic cAMP-dependent protein kinases, type I or II. Messenger RNA levels, notably of the species coding for the enzymes of the peroxisomal beta-oxidation pathway, increased in parallel with ODC and putrescine to reach a maximum also at 36 h. The enzymes of the peroxisomal beta-oxidation pathway, on the other hand, increased more gradually over time to reach a plateau at approximately 7 - 10 days. The magnitude of increase in mRNA (about 7-fold) was comparable to that of peroxisomal beta-oxidation as measured by cyanide-insensitive palmitoyl-CoA-dependent NAD+ reductase activity; comparable increases in the specific content of enoyl-CoA hydratase: beta-hydroxyacyl-CoA dehydrogenase and of peroxisomal thiolase were observed, as determined by SDS electrophoresis. A gradual increase in long-chain acyl-CoA (1.5-fold) followed the increase in beta-oxidation, whereas a 2-fold increase in acid-soluble CoA (free CoA and short-chain acyl-CoA) was seen as early as 36 h. This sequence of changes is at variance with proposals that increased levels of long-chain acyl-CoA mediate induction of peroxisomal beta-oxidation.
Carcinogenesis 1986 Sep
PMID:Relation between induction of ornithine decarboxylase and specific gene expression in rat liver in response to the tumor promoter agent clofibrate. 301 97

The response of cellular NAD+ metabolism to DEN and/or ABA and the carcinogenesis of the liver initiated by DEN and ABA were studied in rats. The liver NAD+ level was depleted by an ip injection of 20 mg or 200 mg/kg body weight of DEN. ABA, administered ip at a dose of 600 mg/kg simultaneously with or 4 hours after DEN, prevented the depletion of NAD+ by DEN. These biochemical findings correlated with the changes of conspicuous intranuclear immunofluorescence of poly(ADP-ribose), which were studied by immunohistochemistry. When initiated by 20 mg/kg body weight DEN and 600 mg/kg ABA and then processed to selection pressure, the liver was found to be capable of developing hepatocellular carcinomas with or without PB promotion. These results suggest that the inhibition of poly(ADP-ribosylation) might lead to irreversible initiation of liver carcinogenesis by DEN in rats.
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PMID:Possible model of liver carcinogenesis using inhibitors of NAD+ ADP ribosyl transferase in rats. 310 Nov 58

Carcinogenesis is blocked by an extraordinary variety of agents belonging to many different classes--e.g., phenolic antioxidants, azo dyes, polycyclic aromatics, flavonoids, coumarins, cinnamates, indoles, isothiocyanates, 1,2-dithiol-3-thiones, and thiocarbamates. The only known common property of these anticarcinogens is their ability to elevate in animal cells the activities of enzymes that inactivate the reactive electrophilic forms of carcinogens. Structure-activity studies on the induction of quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases have revealed that many anti-carcinogenic enzyme inducers contain a distinctive and hitherto unrecognized chemical feature (or acquire this feature after metabolism) that regulates the synthesis of these protective enzymes. The inducers are Michael reaction acceptors characterized by olefinic (or acetylenic) bonds that are rendered electrophilic (positively charged) by conjugation with electron-withdrawing substrates. The potency of inducers parallels their efficiency in Michael reactions. Many inducers are also substrates for glutathione S-transferases, which is further evidence for their electrophilicity. These generalizations have not only provided mechanistic insight into the perplexing question of how such seemingly unrelated anticarcinogens induce chemoprotective enzymes, but also have led to the prediction of the structures of inducers with potential chemoprotective activity.
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PMID:Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. 314 25

Nicotinamide adenine dinucleotide is utilized as the substrate of a chromatin-bound enzyme, poly(ADP-ribose) polymerase. The effects of diethylnitrosamine and/or 3-aminobenzamide, a potent inhibitor of poly(ADP-ribose) polymerase, on the cellular NAD levels in rat liver were investigated. 3-Aminobenzamide (600 mg/kg) administered intraperitoneally was not detectable in the liver within 12 hr after administration; the inhibitor had a calculated half life of 90 min. Diethylnitrosamine reduced the NAD levels in rat liver in a dose-dependent way. The NAD content reached a minimum level at 8 hr, returning to 78% of the control value after 48 hr. The reduction of the NAD levels caused by diethylnitrosamine was completely prevented when 3-aminobenzamide was administered either simultaneously with diethylnitrosamine or 4 hr after diethylnitrosamine treatment. Furthermore, an immunohistochemical study showed that nuclear poly(ADP-ribose) decreased 1 hr after the administration of 3-aminobenzamide. These results suggest that inhibition of poly(ADP-ribosyl)ation is involved in the initiation of liver carcinogenesis by diethylnitrosamine and 3-aminobenzamide.
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PMID:Preventive effect of 3-aminobenzamide on the reduction of NAD levels in rat liver following administration of diethylnitrosamine. 314 98

The metabolism of N-butyl-N-(3-formylpropyl)nitrosamine, a presumptive intermediate metabolite of the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine, by rat liver has been examined. N-Butyl-N-(3-formylpropyl)nitrosamine was metabolized by an NADH-dependent reduction to N-butyl-N-(4-hydroxybutyl)nitrosamine and by an NAD+-dependent oxidation to N-butyl-N-(3-carboxypropyl)nitrosamine. The reduction of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited by pyrazole. The oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was studied further. The rate of oxidation in total rat liver was 3 mumol/min/g liver or 21 nmol/min/mg protein and was similar to that found for the oxidation of propionaldehyde, a model substrate for isozymes of rat liver aldehyde dehydrogenase. The rate of oxidation of N-butyl-N-(3-formylpropyl)nitrosamine by isozymes in rat liver cytosol was 2-2.5 times that found for propionaldehyde. The apparent Km for the NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was 20-30 microM, which is considerably lower than values reported for known substrates of aldehyde dehydrogenase. The NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited 40-50% by 50 microM disulfiram, 60-70% by 100 microM disulfiram, and 50% by 0.4 mM sodium arsenite. These studies show that N-butyl-N-(3-formylpropyl)nitrosamine is very rapidly oxidized to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver by aldehyde dehydrogenase and the results may help to explain why the 3-formylpropyl intermediate has not been directly identified as a metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine in urine or in isolated hepatocytes.
Carcinogenesis 1988 Nov
PMID:Oxidation of N-butyl-N-(3-formylpropyl)nitrosamine to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver and inhibition by disulfiram. 318 Mar 45

Biochemical and microbiological studies were conducted to characterize the mechanism of bacterial formation of N-nitrosomorpholine from morpholine and nitrite at neutral pH. Nitrosating activity was markedly induced when bacteria were cultured anaerobically in minimal culture medium containing nitrate, while the presence of cysteine or tungsten in the medium inhibited induction. Of various metals, coenzymes and inhibitors tested for their effects on in vitro nitrosation of morpholine, potassium cyanide, sodium azide, NAD(P)H and nitrate strongly inhibited nitrosation. Several mutants of Escherichia coli A10 strain were prepared in order to examine whether nitrosation activity is linked to specific loci. Niridazole-resistant mutants, which lack nitroreductase, had as much nitrosating activity as the original E. coli A10, but chlorate-resistant mutants had completely lost this activity. A good correlation was observed between nitrate reductase activity and nitrosating activity in these mutants. These results indicate that bacterial nitrosation is an enzyme-mediated reaction closely associated with molybdenoenzymes such as the nitrate reductase/formate hydrogenlyase system.
Carcinogenesis 1987 Aug
PMID:Biochemical studies on the catalysis of nitrosation by bacteria. 330 Oct 45

The evidence is convincing that oxidants and agents which induce a cellular pro-oxidant state can act as carcinogens, in particular as promoters and progressors. Importantly, infiltrated phagocytes represent a source of oxidants in inflamed tissues. We have studied the mechanism of the promotional action of active oxygen (AO) in mouse epidermal cells JB6 by comparing the non-promotable clone 30 to the promotable clone 41. In order to mimick AO released by phagocytes we used xanthine/xanthine oxidase as a source of extracellular superoxide and hydrogen peroxide. We found that AO stimulated the growth only of promotable clone 41 after an initial period of moderate inhibition while it was strongly cytostatic for non-promotable clone 30. Reasons for the higher cytostatic effect of AO on the non-promotable clone 30 were discovered when we measured DNA strand breakage and poly ADP-ribosylation of chromosomal proteins. At equal doses AO induced 4-5 times more DNA breaks in clone 30 in reactions which required iron--and probably also calcium--ions. The higher amount of DNA breakage in clone 30 was reflected in a higher extent of poly ADP-ribosylation. Excessive DNA breakage and poly ADP-ribosylation which causes the depletion of NAD and ATP may be responsible for the strong cytostatic effect of AO in clone 30. We conclude that differential resistance to the cytostatic/cytotoxic effect of AO in part determines the promotability of mouse epidermal cells JB6.
Carcinogenesis 1988 Feb
PMID:Active oxygen induced DNA strand breakage and poly ADP-ribosylation in promotable and non-promotable JB6 mouse epidermal cells. 333 7

Diethylnitrosamine following partial hepatectomy followed by phenobarbital promotion was used to study changes in aldehyde dehydrogenase (ALDH) activity during rat hepatocarcinogenesis. Over a period of 350 days, animals were killed at intervals and the ALDH phenotype of normal liver and any lesions was characterized by histochemical analysis, total activity assays and gel electrophoresis using propionaldehyde and NAD+ to detect normal liver ALDH activities, and benzaldehyde and NADP+ for tumor-associated ALDH. In contrast to previously tested protocols, no significant changes in ALDH activity were demonstrable by histochemistry or total activity assays in preneoplastic livers. However, nine of 16 (56%) of the hepatocellular carcinomas examined expressed the tumor-associated ALDH phenotype. The present results are integrated with previous observations as a hypothesis explaining the roles of initiation and promotion in expression of the tumor-associated aldehyde dehydrogenase phenotype.
Carcinogenesis 1987 Jun
PMID:Changes in aldehyde dehydrogenase activity during diethylnitrosamine-initiated rat hepatocarcinogenesis. 360 75

The 1,2-dithiol-3-thiones are a class of five-membered cyclic sulfur compounds which have chemotherapeutic and chemoprotective properties. The parent 1,2-dithiol-3-thione nucleus and a series of six substituted analogs all induced NAD(P)H: quinone reductase (EC 1.6.99.2) activity and elevated glutathione levels in Hepa 1c1c7 murine hepatoma cells in culture thereby enhancing detoxification potential. These analogs included monosubstituted derivatives with phenyl, p-methoxyphenyl or 2-pyrazinyl groups at C-4 or C-5, and disubstituted compounds bearing phenyl or 2-pyrazinyl moieties at C-5 and an additional methyl group at C-4. This system can be used as an in vitro model for the study of the specificity and mechanism of action of the 1,2-dithiol-3-thiones as already demonstrated for several other classes of chemoprotective agents. The 1,2-dithiol-3-thiones also elevated quinone reductase and glutathione levels in the Hepa 1c1c7 cell mutants (BPrc1 and TAOBPrc1) that are defective in aryl hydrocarbon receptor functions. We conclude that the 1,2-dithiol-3-thiones are largely concerned with the stimulation of metabolic inactivation of electrophiles.
Carcinogenesis 1986 Jun
PMID:1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. 370 58

3-Aminobenzamide (3AB) is a competitive inhibitor of poly-(ADP-ribose) polymerase. It will interact synergistically with certain monofunctional alkylating agents to increase the frequency of sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells. 3AB will also increase the baseline SCE frequency in exposed cells. The extent of interaction between 3AB and monofunctional alkylating agents varies depending on the alkylating agent used and appears to be due to the different amounts of membrane damage produced by the alkylating agents. In this study, exogenously added beta-NAD+ was found to reduce substantially SCE frequency in cells that had been treated with combinations of 3AB and methyl methanesulfonate (MMS) but not in cells treated with 3AB and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MMS produces more cell membrane damage than MNNG at equitoxic doses. beta-NAD+ is the substrate for ADP-ribosylation and normally does not freely diffuse into cells. beta-NAD+ had no significant effect on SCE induction in intact cells or in cells treated with either 3AB or alkylating agent alone. In contrast to beta-NAD+, exogenously added alpha-NAD+, which is an inhibitor of poly(ADP-ribose) polymerase, increased SCE frequency in MMS-treated cells. Thus the interaction between 3AB and certain monofunctional alkylating agents in SCE formation is apparently due to cell membrane permeabilization and the loss of intracellular NAD+ which in turn probably results in a greater inhibition of ADP-ribosylation in the presence of 3AB.
Carcinogenesis 1986 Jan
PMID:Potentiation of alkylation-induced sister chromatid exchange frequency by 3-aminobenzamide is mediated by intracellular loss of NAD+. 394 37


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