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

To characterize the promoting activity of thiobenzamide (TB), a thiono-sulfur-containing xenobiotic, rats of both sexes were treated with the compound for 4 or 8 weeks after an initiating dose of diethyl-nitrosamine. The number, area (volume), and phenotypic complexity of the enzyme-altered hepatocyte foci were studied in serial sections stained with hematoxylin/eosin and reacted for glycogen, iron, and gamma-glutamyltranspeptidase activity. The TB-induced changes on the drug metabolizing systems were also investigated. The main findings were: When fed in a dose range of 500-2,000 mg/kg of diet, TB induced a number of foci greater than controls, especially in female rats. Benzamide, a major TB metabolite, was ineffective. The appearance of hepatocyte foci upon TB feeding was nearly synchronized. An increase of the phenotypic complexity of the hepatocyte foci occurred only during the first 4 weeks of TB administration; it correlated with an increase in size. The liver microsome content of cytochrome P-450 as well as the activity of many monooxygenases was decreased, some of the phase II reactions being increased. In conclusion TB behaves as an efficient promoter of liver carcinogenesis, possibly as a consequence of an induced adaptive response.
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PMID:Characterization of the promoting activity of thiobenzamide on liver carcinogenesis. 378 20

Some aspects of the age-dependence of the metabolic activation of three classes of chemical carcinogen (polycyclic hydrocarbons, N-nitrosamines and aromatic amines) are considered. In general, and as with other xenobiotic agents, metabolism is low in fetal tissue, increases with maturation and decreases in old age. In a single-dose hydrocarbon carcinogenesis model system, a decrease in tumour incidence is correlated with increasing age at treatment, although other factors such as cell turnover at the time of carcinogen treatment are also correlated with this disease. Evidence is presented, in addition, that the induction of rat hepatic O6-methylguanine-DNA methyltransferase activity by the metabolism-requiring hepato-carcinogen 2-acetylaminofluorene increases with age.
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PMID:The effects of age on the metabolism of chemical carcinogens and inducibility of O6-methylguanine methyltransferase. 383 Aug 77

The activities of several enzymes which metabolize xenobiotics were measured and compared in freshly isolated rabbit Clara cells (50-70% purity) and alveolar type II cells (80-95% purity) or microsomal preparations from the isolated cell fractions. The presence of 1 mM nicotinamide in protease and cell isolation buffers increased significantly 7-ethoxycoumarin (7-EC) deethylase and epoxide hydrolase activities in the isolated Clara and type II cells. Isolated Clara cell fractions metabolized 7-EC to umbelliferone at a rate of 241 +/- 27 pmoles/mg prot/min (mean +/- S.E., N =5), while the 7-EC deethylation rate in type II cells was 111 +/- 15 pmoles/mg prot/min. Coumarin hydroxylation activity, however, was more than ten times greater in the Clara cells than in the type II cells on a per mg cellular protein basis. N-oxidation of N,N-dimethylaniline, catalyzed by a flavin monooxygenase, was about 2 times as great in microsomes of Clara cells as in microsomes of type II cells. Epoxide hydrolase activity with benzo(a)pyrene 4,5-oxide as substrate was about 10 times higher in Clara cells than in type II cells. Because of the greater cellular, structural and functional heterogeneity in lung, differential distribution of enzymes responsible for xenobiotic metabolism in this tissue may contribute to cell selective chemical toxicity and carcinogenesis.
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PMID:Cytochrome P-450 monooxygenase, epoxide hydrolase and flavin monooxygenase activities in Clara cells and alveolar type II cells isolated from rabbit. 391 26

The purpose of the present investigation was to determine the effects of dietary selenium deficiency or excess on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary neoplasia in rats and to delineate whether selenium-mediated modification of mammary carcinogenesis was associated with changes in carcinogen:DNA adduct formation and activities of liver microsomal enzymes that are involved in xenobiotic metabolism. Female Sprague-Dawley rats were divided into three groups from weaning and were maintained on one of three synthetic diets designated as follows: selenium deficient (less than 0.02 ppm); selenium adequate (0.2 ppm); or selenium excess (2.5 ppm). For the DMBA binding and DNA adduct studies, rats were given a dose of [3H]DMBA p.o. after 1 month on their respective diets. Results from the liver and the mammary gland indicated that neither selenium deficiency nor excess had any significant effect on the binding levels, which were calculated on the basis of total radioactivity isolated with the purified DNA. Furthermore, it was found that dietary selenium intake did not seem to affect quantitatively or qualitatively the formation of DMBA:DNA adducts in the liver. Similarly, in a parallel group of rats that did not receive DMBA, the activities of aniline hydroxylase, aminopyrine N-demethylase, and cytochrome c reductase were not significantly altered by dietary selenium levels. Concurrent with the above experiments, the effect of dietary selenium intake on carcinogenesis was also monitored. Results of this experiment indicated that selenium deficiency enhanced mammary carcinogenesis only when this nutritional condition was maintained in the postinitiation phase. Likewise, an excess of selenium intake inhibited neoplastic development only when this regimen was continued after DMBA administration. In either case, deficient or excess selenium at the time of carcinogenic insult failed to produce a significant effect on subsequent tumor yield, if selenium intake was returned to normal during the proliferative phase of tumor growth. Based on the results of these studies, it is suggested that selenium-mediated modification of mammary tumorigenesis is not exerted via alterations in carcinogenic initiation (i.e., metabolism or DNA adduct formation).
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PMID:Effects of selenium on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis and DNA adduct formation. 391 75

A single exposure to a wide range of concentrations (10(-15)-10(-4) mol/l) of the tumour promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phenobarbital (PB) significantly stimulated the flow into DNA synthesis and mitosis of neonatal rat hepatocytes in 4-day-old primary cultures kept in high-calcium (1.8 mmol/l) Eagle's FBS-MEM. Maximal effects were observed in the dose range 10(-12)-10(-6) mol/l. Moreover, both xenobiotics retained their full mitogenic effectiveness when given to hepatocytes incubated in calcium-deficient (0.01 mmol/l) FBS-MEM, thereby evoking a neoplastic phenotype in otherwise normal (i.e., non-initiated) cells. Proliferation kinetic studies showed that TPA and PB acted according to the actual cell cycle setting of the cells: they committed a fraction of the quiescent (GO) hepatocytes to grow, and enabled hepatocytes previously poised at the G1/S and G2/M boundaries to start cycling again, but exerted no influence on liver cells already engaged by themselves in active cycling. These diverse activities of TPA and PB were independent of serum (growth) factors; they were also fully elicited in hepatocytes grown in synthetic media (Eagle's MEM or HiWoBa2000), and were not changed by the addition of a mitogenically effective dose (10(-10) mol/l) of epidermal growth factor/urogastrone (EGF) with or without FBS. Conversely, the addition of the specific plasmalemmal calcium chelator, EGTA, or displacer, La3+, or of the anticalmodulin drugs, W-13 and calmidazolium (or R24571: an agent hardly entering cells) fully inhibited the mitogenic activities of tumour promoters in quiescent and intra-cycle-blocked hepatocytes, while having no effect on untreated or xenobiotic-treated liver cells already cycling by themselves. Such inhibitory effects were in all instances independent of the actual extracellular calcium concentration and took place according to time-related double kinetics. Hence, xenobiotic-activated processes taking place at the plasmalemmal level and involving the activation of calcicalmodulin-dependent enzymes were of critical importance for both the G0/G1 and G1/S transitions in primary hepatocytes.
Carcinogenesis 1985 Jun
PMID:The stimulation by the tumour promoters 12-O-tetradecanoylphorbol-13-acetate and phenobarbital of the growth of primary neonatal rat hepatocytes. 392 34

The influence of eleven xenobiotics on the activity and amount of hepatic microsomal epoxide hydrolase was determined. Activity was assayed using three different substrates after rats were fed, throughout 3 weeks, diets containing one of six hepatocarcinogens, viz. 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, 4'-fluoro-4-dimethylaminoazobenzene, thioacetamide, aflatoxin B1 and ethionine. Five hepatocarcinogens induced activity 4- to 10-fold; ethionine was relatively ineffective as an inducer. Two non-carcinogenic analogues of hepatocarcinogens, viz. fluorene and p-aminoazobenzene, caused no appreciable increase in enzyme activity, but phenobarbital, barbital and 1-naphthylisothiocyanate induced activity 2- to 3-fold. All eleven xenobiotics increased the amount of microsomal epoxide hydrolase 2- to 9-fold when examined immunochemically using either a radial diffusion assay or an enzyme-linked immunosorbent assay (ELISA). Serum glutamic oxaloacetic acid transaminase activity was not appreciably elevated by feeding ten of the xenobiotics, suggesting that inductions were not owing to toxicity. Using ELISA, microsomal epoxide hydrolase was detected in post-microsomal (PM) supernatant fractions from control rat liver, thus confirming an earlier report by Gill et al. [Carcinogenesis 3, 1307 (1982)]. The eleven xenobiotics induced the amount of ELISA-detectable antigen in PM supernatant fractions by 3- to 34-fold. Longer centrifugation of PM supernatant fractions yielded a pellet fraction that contained 92 +/- 1.2% of the ELISA-detectable antigen irrespective of the xenobiotic regimen. Relationships between xenobiotic induction of microsomal epoxide hydrolase activity and amount and hepatocarcinogenesis are discussed.
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PMID:Assessment of rat liver microsomal epoxide hydrolase as a marker of hepatocarcinogenesis. 400 95

The probability of obtaining a tumor in a carcinogenesis bioassay depends mainly on the time on test and on the dose of carcinogen used. There is very limited data on the shape of this surface or reliable data on dose-response or time on test-response relationships. Ullrich's data on tumor induction by low dose radiation shows a variety of shapes of curve depending on the tissue chosen for investigation. As radiation probably does not concern the processes involved in xenobiotic metabolism, these observations clearly demonstrate that factors other than metabolism are important. An attempt is made to discuss the shape of the dose-response curve in relation to a number of factors including the background incidence of tumors in a tissue, mechanisms of "nongenotoxic" or toxicity-related carcinogenesis, and xenobiotic activation of carcinogens.
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PMID:Dose relationships in experimental carcinogenesis: dependence on multiple factors including biotransformation. 404 66

Carcinogenesis involves a complex interplay of both hereditary and environmental factors. With the exception of some cancers which may be inherited through an autosomal dominant gene (e.g., retinoblastoma), cancer causation is controlled by a multitude of genes. The murine Ah complex is an example of a well-characterized model system for studying genetic factors for carcinogenesis in mice. The Ah complex controls the induction of several xenobiotic-metabolizing enzyme activities by, e.g., polycyclic aromatic hydrocarbons (PAHs). Allelic differences at the Ah locus are associated with increased individual risk for cancer and mutation. The polyamines and their biosynthetic enzymes, especially ornithine decarboxylase (ODC), are useful probes in the study of carcinogenesis. The available evidence supports the theory that the induction of ODC activity is an essential factor in mouse skin tumorigenesis. In contrast, ODC induction is not an essential prerequisite in the induction of enzymes involved in converting carcinogens of the PAH-type to reactive intermediates capable of binding to DNA. The possible involvement of the polyamines and ODC in cancer initiation and promotion, in DNA repair processes and in genetic factors that might influence them are discussed in this review.
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PMID:Genetically determined differences in the response to carcinogens of aryl hydrocarbon hydroxylase and ornithine decarboxylase. 636 67

The effect of a surgical intervention, portocaval anastomosis (PCA) has been investigated in three different phases of a triphasic protocol of rat hepatocarcinogenesis. This protocol consists of the i.p. injection of 200 mg/kg of diethylnitrosamine (initiation) followed 2 weeks later by a 2 weeks diet with 2-acetylaminofluorene (2-AAF) and in the middle a necrogenic dose of CC14 (selection). One week later, a promoter such as phenobarbital (PB) is given chronically (promotion). PCA or a sham operation is performed 5 months before the end of the experiment. PCA alone does not induce hyperplastic nodules, nor does it when rats are initiated 5 weeks before. However, PCA alters the evolution of established nodules: it can act as a promoter like PB. Indeed, 5 months after initiation and selection, the number of rats bearing hepatocarcinomas is zero out of seven with a sham operation and six out of seven with PCA performed one week after the end of the selection. The combination of PCA and PB is more potent than PB or PCB alone since six out of six, five out of eight and six out of seven rats, respectively, bear malignant liver tumours. Thus PCA, which induces many systemic perturbations, has a promoting effect. This suggests that the chronic administration of a xenobiotic is not the only way to promote cancer development.
Carcinogenesis 1984 Sep
PMID:Promoting effect of portocaval anastomosis in rat hepatocarcinogenesis. 646 5

Biotransformation of lipophilic xenobiotics may lead to formation of reactive intermediates which can give rise to irreversible toxic events such as carcinogenesis, mutagenesis, teratogenesis, and tissue necrosis. In recent years considerable attention has been paid to the problem of testing for these effects. Short-term mutagenicity tests have been shown to have value for predicting the occurrence of delayed toxic effects in mammals following administration of indirectly acting harmful xenobiotics. In any test system the capacity to bioactivate the compound under test is a necessary prerequisite, and in most short-term test assays this is provided for by adding a metabolic activation system generally consisting of the 9,000 g supernatant fraction of a rat liver homogenate supplied with cofactors. The fruitfly Drosophila melanogaster constitutes an organism well-suited for mutagenicity testing, and it was shown that a number of precarcinogens evoke mutagenic effects in this species. Thus Drosophila is apparently able to metabolize xenobiotics to reactive intermediates, which in turn induce mutagenicity. However, knowledge about the presence and characteristics of the xenobiotic-metabolizing enzymes involved is lacking. Since knowledge of these enzymes contributes to the evaluation and interpretation of observed mutagenic events, this paper described studies concerning some important xenobiotic-metabolizing enzymes of Drosophila. Files were homogenized and subcellular fractions were investigated with respect to enzymatic activities. It was possible to demonstrate cytochrome P-450 and some related mixed-function oxidase activities. Cytochrome b5, epoxide hydrolase, and glutathione S-transferase are also present, while preliminary experiments suggest the presence of UDP-glucosyltransferase and phosphotransferase activities. The enzymes which have been found are discussed with respect to their similarities with rat liver enzymes and their relevance for mutagenicity testing with Drosophila melanogaster.
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PMID:Biotransformation of xenobiotics in Drosophila melanogaster and its relevance for mutagenicity testing. 678 78


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