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

In vitro model systems have recently been developed to investigate the toxicity of chemical, microbial and physical agents in normal human tissues and cells from many of the major tissue sites of high cancer incidence. Pathobiological endpoints used in these studies include alterations in incorporation rates of precursors into DNA, RNA and protein, in the clonal growth rate of cultured cells and in DNA structure (e.g. single-strand breaks, DNA-protein crosslinks and chemical-DNA adducts) and the induction of differentiation, chromosomal and karyotypic abnormalities, mutations and neoplastic transformation. These systems have been used to study a variety of complex mixtures and individual substances, including cigarette smoke components such as benzo[a]pyrene and N-nitrosamines, formaldehyde, fecapentaenes, asbestos, and nickel and chromium ions. In addition, increasing awareness of the role of oncogenes in human carcinogenesis has led to studies involving transfection experiments with oncogenes and hepatitis B viral genes in normal human cells.
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PMID:Genotoxicity of chemical and physical agents in cultured human tissues and cells. 378 23

Hydrazine is carcinogenic to the mouse and rat, but three earlier studies have reported no carcinogenicity of hydrazine in the hamster. Administration of hydrazine to mice, rats and hamsters results in rapid methylation of liver DNA guanine for which endogenous formaldehyde appears to be the source of the methyl moiety. Hamsters were given hydrazine sulfate at 170, 340 and 510 mg/l in the drinking water for 2 years [average dose of 4.6, 8.3 and 10.3 mg hydrazine (free base)/kg body wt over the 2-year period], during which levels of methylation of DNA guanine in liver, kidney and lung, and histopathologic examinations of these tissues were carried out; dimethylnitrosamine, as a positive control, was administered at 10 mg/l in the drinking water (average dose of 1.1 mg/kg body wt over the 4-month measurement period). Both 7-methylguanine and O6-methylguanine were readily detectable at 6 months exposure in hamsters given hydrazine or dimethylnitrosamine; in hydrazine-treated animals only trace amounts of these bases could be detected after 12 months exposure; these bases were again detected in liver DNA at exposure times of 18 and 24 months. Hepatocellular carcinomas were observed in hamsters treated at the highest dose of hydrazine sulfate after 78 weeks of exposure; the incidence of liver cancer was dose-related over the course of the experiment: 32% for hamsters exposed to 510 mg hydrazine sulfate/l, 12% for 340 mg/l and none at 170 mg/l. Hamsters given dimethylnitrosamine developed high levels of 7-methylguanine and even higher levels of O6-methylguanine and both liver cholangiocellular carcinomas (73% incidence), as reported before, and hepatocellular carcinomas (27% incidence), a new finding. These results demonstrate for the first time that hydrazine is a liver carcinogen in the hamster and provide new information regarding the accumulation of DNA damage during the entire induction period for the carcinomas.
Carcinogenesis 1987 Mar
PMID:Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. 381 39

Relatively short-term treatment (8 weeks) of rats with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/l) was shown to adequately initiate gastric carcinogenesis when 10% NaCl was simultaneously administered in the diet. Utilizing this MNNG plus high salt diet as the initiation stage of a two-step protocol, it was also established that subsequent dietary administration of NaCl (10% of the diet) for 32 weeks tended to enhance tumor development in the glandular stomach. Similar tumor promoting activity was demonstrated for other mucosal damaging agents, such as potassium metabisulfite and formaldehyde. Biological changes of the gastric mucosa were examined after chronic administration or a single oral intubation of NaCl. Morphological lesions observed included diffuse mild erosions, atrophy of the glands, and hyperplasia of the foveolar epithelium when given 10% NaCl diet chronically. After a single oral intubation of NaCl, increased tritiated thymidine labeling index and ornithine decarboxylase (ODC) activity were observed in both pyloric and fundic mucosa. No remarkable effects of NaCl were observed on the forestomach or duodenal mucosa. These results suggest that NaCl exerts an enhancing effect at both initiation and promotion steps within the two stage model system of the gastric carcinogenesis, and that these effects of NaCl are possibly related to its mucosal damaging activity.
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PMID:Enhancing effects of dietary salt on both initiation and promotion stages of rat gastric carcinogenesis. 391 94

Administration of the hepatotoxin and carcinogen, inorganic hydrazine, to rodents results in the formation of 7-methylguanine and O6-methylguanine in liver DNA; co-administration of [methyl-14C]methionine or [14C]formate with the hydrazine labels the methylguanines, suggesting involvement of the 1-carbon pool in the methylation process. The present study investigates the proposal that the methylation mechanism involves reaction of hydrazine with endogenous formaldehyde to yield formaldehyde hydrazone, which could be metabolized to the potent methylating agent diazomethane. Hamsters were pretreated with methanol, ethanol or cyanamide to alter the endogenous hepatic aldehyde levels prior to administration of hydrazine. Formaldehyde levels were refractory to the pretreatments; hepatic acetaldehyde levels were increased, but hydrazine administration under such conditions did not result in the formation of ethylated guanines in DNA. Methanol and ethanol inhibited hydrazine-induced methylation of DNA. Hydrazine incubated with liver S9 fraction and calf thymus DNA induced the formation of 7-methylguanine and O6-methylguanine when formaldehyde was present in the incubation system; substitution of formaldehyde with acetaldehyde in the incubation medium did not result in any detectable alkylation of DNA. Both liver microsomal and cytosolic fractions demonstrated heat-labile activity in supporting the hydrazine-induced methylation process. Tetraformyltrisazine, or a similar reaction product of hydrazine and formaldehyde, may be a more important intermediate than formaldehyde hydrazone in the hydrazine-induced methylation of DNA.
Carcinogenesis 1986 Mar
PMID:The role of formaldehyde in hydrazine-induced methylation of liver DNA guanine. 394 26

Hydrazine induces methylation of target-organ DNA guanine; the methylation mechanism was proposed to involve reaction of hydrazine with endogenous formaldehyde. One possible condensation product of hydrazine and formaldehyde is tetraformyltrisazine (TFT). TFT administered to Sprague-Dawley rats produced 7-methylguanine and O6-methylguanine in liver DNA at rates of formation and times to maximal methylguanine levels similar to those observed after hydrazine administration. TFT administration, however, resulted in greater amounts of methylguanines than did hydrazine on a molar basis, suggesting that TFT is perhaps a more proximal intermediate in hydrazine-induced methylation. The metabolic activation of TFT and hydrazine-plus-formaldehyde to methylating intermediates was detectable in in vitro systems containing as little as 0.2 mM TFT or 1 mM hydrazine-plus-formaldehyde, the lowest concentrations yet tested. The other major condensation product of hydrazine and formaldehyde, formalazine, also methylated liver DNA in vivo, but this polymer forms under conditions that would not be expected under in vivo administration of hydrazine. A novel pathway is proposed for the generation of a carbocation in hepatocytes exposed to hydrazine, consisting of condensation of hydrazine and formaldehyde to form TFT or formaldazine and/or formaldehyde hydroxymethylhydrazone and involves methylazomethanol as an intermediate.
Carcinogenesis 1986 Mar
PMID:Tetraformyltrisazine and hydrazine-induced methylation of liver DNA guanine. 394 27

Using an in vitro assay system for measuring 7-methylguanine formation in DNA, it was demonstrated that N-nitroso(2-oxopropyl)propylamine (NOPPA) is converted into a methylating agent by a microsomal, cytochrome P-450 dependent mixed function oxidase from rat liver. Formation of propionaldehyde, but not formaldehyde, in this assay system, indicated that a single alpha-oxidation reaction on the propyl side chain of NOPPA leads to the formation of a methylating agent. A mechanism for this reaction is proposed.
Carcinogenesis 1985 Feb
PMID:Mechanism of DNA methylation by N-nitroso(2-oxopropyl)propylamine. 397 84

Dietary-related indoles, isothiocyanates, and the allyl isothiocyanate glucosinolate, sinigrin, were administered to F344 rats in the diet for 2 weeks (chronic protocol) or by gavage 2 h before sacrifice (acute protocol) and the effects of these pretreatments on the alpha-hydroxylation of two carcinogenic nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were evaluated. alpha-Hydroxylation was measured in vitro by quantitation of formaldehyde formation upon incubation of the nitrosamines with liver microsomes, and in vivo by quantitation of levels of 7-methylguanine and O6-methylguanine in hepatic DNA, 4 h after nitrosamine treatment. Compounds shown to be inhibitory in the in vitro assay were selected to be further evaluated using the in vivo assay. The results of the in vitro assays showed that indoles were inducers of the demethylation of both nitrosamines. Indole, L-tryptophan and indole-3-carbinol were strong inducers of NDMA and NNK demethylation, respectively. In contrast, isothiocyanates such as phenethyl isothiocyanate and phenyl isothiocyanate demonstrated a wide range of inhibitory activities toward demethylation of these nitrosamines in both the acute and chronic studies. Chronic, but not acute, pretreatment with sinigrin also caused a significant decrease in the demethylation of NDMA and NNK. In view of their promising inhibitory activities, the effects of phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin on the in vivo methylation of DNA by NDMA and NNK were evaluated. The results were parallel to those obtained in the in vitro assays. Phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin generally inhibited the formation of 7-methylguanine and O6-methylguanine in rat hepatic DNA. The results of this study suggest that these compounds could be anticarcinogenic to NDMA and NNK.
Carcinogenesis 1985 Apr
PMID:Effects of dietary indoles and isothiocyanates on N-nitrosodimethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone alpha-hydroxylation and DNA methylation in rat liver. 398 60

Lipid peroxidation aldehydes of the 4-hydroxy-alpha, beta-unsaturated type, as well as the tobacco-smoke related alpha, beta-unsaturated aldehyde, acrolein, were highly cytotoxic and decreased the intracellular thiol content in cultured human bronchial fibroblasts after treatment with micromolar concentrations. In comparison, formaldehyde and acetaldehyde were less toxic and 100- to 300-fold higher doses were required to affect cell survival or thiol levels. The unsaturated aldehydes also markedly inhibited the DNA repair enzyme O6-methylguanine-DNA methyltransferase known to have a cysteine residue in its active site, but had no effect on the activity of uracil-DNA glycosylase. Our results indicate that reactive aldehydes of either exogenous or endogenous origin have direct cytotoxic effects and may also make cells more susceptible to other toxic chemicals due to an impairment in cellular defense mechanisms, e.g., DNA repair and detoxification by systems requiring glutathione.
Carcinogenesis 1985 Dec
PMID:Cytotoxicity, thiol depletion and inhibition of O6-methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts. 406 50

1. The incorporation of methyl groups into histones from dimethylnitrosamine and from methionine was studied by injection of the labelled compounds, isolation of rat liver and kidney histones, and analysis of hydrolysates by column chromatography. 2. Labelled methionine gave rise to labelled in-N-methyl-lysine, di-in-N-methyl-lysine and an amino acid presumed to be omega-N-methyl-arginine. 3. Administration of labelled dimethylnitrosamine gave rise to labelled S-methylcysteine, 1-methylhistidine, 3-methylhistidine and in-N-methyl-lysine derived from the alkylating metabolite of dimethylnitrosamine. In addition, labelled formaldehyde released by metabolism of dimethylnitrosamine leads to the formation of labelled S-adenosylmethionine, and hence to labelling of in-N-methyl-lysine, di-in-N-methyl-lysine and omega-N-methylarginine by enzymic methylation. 4. The formation of in-N-methyl-lysine by alkylation of liver histones was confirmed by using doubly labelled dimethylnitrosamine to discriminate between direct chemical alkylation and enzymic methylation via S-adenosylmethionine. These experiments also suggested the possibility that methionine residues in the histones were alkylated to give methylmethionine sulphonium residues. 5. The extent of alkylation of liver histones was maximal at about 5h after dosing and declined between 5 and 24h. The methylated amino acids resulting from direct chemical alkylation were preferentially lost: this is ascribed to necrosis of the more highly alkylated cells. 6. Liver histones were about four times as alkylated as kidney histones; the extent of alkylation of liver histones was similar to that of liver total nuclear proteins. 7. Methyl methanesulphonate (120mg/kg) alkylated liver histones to a greater extent than did dimethylnitrosamine. Diethylnitrosamine also alkylated liver histones. 8. The results are discussed with regard to the possible effects of alkylation on histone function, and the possible role of histone alkylation in carcinogenesis by the three compounds.
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PMID:Methylation of nuclear proteins by dimethylnitrosamine and by methionine in the rat in vivo. 513 29

Prostaglandin endoperoxide synthase catalyzed the oxidation of tetramethylhydrazine to the tetramethylhydrazine radical cation, as detected by electron spin resonance spectroscopy. Oxidation of tetramethylhydrazine by prostaglandin endoperoxide synthase also resulted in the N-demethylation of tetramethylhydrazine leading to the formation of formaldehyde. Both the radical and formaldehyde formation were dependent on arachidonic acid, inhibited by indomethacin, and supported by 15-hydroperoxyarachidonic acid, indicating that the metabolism was peroxidative. We propose that tetramethylhydrazine undergoes two sequential one-electron oxidations yielding an iminium cation, which is then hydrolyzed to yield formaldehyde. Metabolism of hydrazines by prostaglandin endoperoxide synthase may be of importance in tissue containing low mixed-function oxidase activity.
Carcinogenesis 1983 Oct
PMID:A free radical mediated cooxidation of tetramethylhydrazine by prostaglandin hydroperoxidase. 631 52


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