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)

Sequential carcinogen treatment (diethylnitrosamine/partial hepatectomy followed by 2-acetylaminofluorene (2-AAF] induced multiple hepatocarcinomas in rats with 100% certainty within a year. Enzyme-altered lesions, i.e. gamma-glutamyltranspeptidase (GGT)-positive and/or ATPase-negative cell foci, were numerous already at 8 weeks, and suspensions of purified hepatocytes isolated (by collagenase perfusion) at this time contained 30-40% GGT-positive cells. These hepatocyte suspensions were markedly deficient with respect to autophagic protein degradation (in comparison with cell suspensions from normal rats), and the cells lost less protein and survived much better than normal hepatocytes in culture under conditions of amino acid deprivation (which activates the autophagic mechanism). The anabolic advantage of reduced autophagy may possibly contribute to the selective outgrowth of preneoplastic cells during the earliest stage of liver carcinogenesis. Inclusion of the autophagy inhibitor 3-methyladenine in the culture medium elevated the survival of normal hepatocytes up to the level seen with hepatocytes from carcinogen-treated animals, suggesting that protection of normal cells by autophagy suppression may be a potentially interesting therapeutic principle.
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PMID:Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. 285 48

Effects of initiators and promoters of hepatocarcinogenesis on UDP-glucuronyltransferase and arylhydrocarbon hydroxylase were investigated in foci of altered hepatocytes. A single administration of N-nitrosomorpholine (75 mg/kg, 24 h after partial hepatectomy) was used for initiation and chronic administration of phenobarbital (0.1% in tap water) for promotion. Histological evidence indicated that ATPase-negative, gamma-glutamyltranspeptidase-positive, and UDP-glucuronyltransferase-positive foci were highly correlated. Based on this evidence ATPase-negative foci were used as a guide to monitor early lesions and to microdissect lyophilized foci and extra-focal tissue. It was found that treatment with N-nitrosomorpholine led to a permanent increase of UDP-glucuronyltransferase activity in foci tissue (3- to 5-fold, detected 180 and 330 days after initiation). In contrast, arylhydrocarbon hydroxylase activity was decreased by 50%. Administration of phenobarbital further increased UDP-glucuronyltransferase activity in focal tissue (up to 9-fold, compared with control liver). However, this further increase of enzyme activity by phenobarbital was reversible. The results suggest that (i) initiation by chemical carcinogens leads to permanent alterations of drug metabolizing enzymes, consistent with increased toxin-resistance of initiated hepatocytes, and (ii) chronic administration of phenobarbital markedly enhances gene expression of UDP-glucuronyltransferase in initiated hepatocytes.
Carcinogenesis 1985 Apr
PMID:Effects of N-nitrosomorpholine and phenobarbital on UDP-glucuronyltransferase in putative preneoplastic foci of rat liver. 285 28

Rat hepatocytes maintained for up to 6 days in primary culture were used to test a variety of xenobiotics and steroids for effects on the activity of gamma-glutamyltranspeptidase (GGT) in normal cells. In control cultures GGT activity was low and increased slowly with time. When added to cultures for 5 days, a variety of xenobiotics and steroids increased GGT activity to levels 2- to 6-times those of control cultures. Induction of GGT was potentiated for most test compounds by 20-30 nM dexamethasone and diminished by nicotinamide or adenosine-3',5'-monophosphate. Effective non-genotoxic inducers included phenobarbital and some structurally related compounds, p,p'-dichlorodiphenyltrichloroethane,alpha- and gamma-hexachlorocyclohexanes, Aroclor 1254, butyl hydroxytoluene, nafenopin, various estrogens, progesterone, pregnenolone-16 alpha-carbonitrile and cyproterone acetate. A number of compounds including barbituric acid, butyl hydroxyanisole, acetaminophen, saccharin, caffeine, clofibrate and some bile acids failed to induce GGT. Except for 2-acetylaminofluorene and diethylnitrosamine, genotoxic compounds tested did not increase GGT. The results establish that a structurally diverse group of xenobiotics and steroids, many of which are considered to be liver tumour promoters, may directly enhance GGT gene expression in normal hepatocytes. Thus, a variety of compounds used in experimental studies of liver cancer induction as promoters may elevate GGT by mechanism(s) not necessarily related to carcinogenesis.
Carcinogenesis 1985 May
PMID:Induction of gamma-glutamyl transpeptidase in primary cultures of normal rat hepatocytes by liver tumor promoters and structurally related compounds. 286 Sep 80

The role of sulfation of the carcinogen N-hydroxy-2-acetyl-aminofluorene in the initiation phase of liver-tumor formation was studied in an initiation-promotion model modified from the Solt and Farber system (Cancer Res., 43, 188-191, 1983). The effect of the sulfation inhibitor pentachlorophenol on the induction by N-hydroxy-2-acetylaminofluorene of gamma-glutamyltranspeptidase positive foci of cells (regarded as a population of cells from which neoplastic cells will develop) was determined. Inhibition of sulfation did not prevent the induction of gamma-glutamyltranspeptidase positive foci in rat liver; on the contrary, an increase was observed. Since it is known that inhibition of sulfation of N-hydroxy-2-acetylaminofluorene prevents the formation of covalently-bound 2-acetylaminofluorene adducts to proteins, RNA, and DNA in the rat liver (Meerman et al., Carcinogenesis, 2, 413-416, 1981), the results from this study suggest that deacetylated, 2-aminofluorene adducts to DNA are responsible for initiation of gamma-glutamyltranspeptidase positive foci in the rat liver (because formation of these adducts is not affected by pentachlorophenol). After initiation with a single dose of N-hydroxy-2-acetylaminofluorene, proliferation of 'oval cells' was observed only 1 week after administration of the carcinogen. This was not observed in the livers of rats pre-treated with pentachlorophenol in which the largest number of foci develops. These data therefore suggest that 'oval cells' are not involved in the development of gamma-glutamyltranspeptidase positive foci.
Carcinogenesis 1985 Jun
PMID:The initiation of gamma-glutamyltranspeptidase positive foci in the rat liver by N-hydroxy-2-acetylaminofluorene. The effect of the sulfation inhibitor pentachlorophenol. 286 Sep 81

The biological mechanisms by which pyrrolizidine alkaloids contribute to initiation and nodule selection (promotion) steps in hepatic carcinogenesis were studied in male Fischer 344 rats. Lasiocarpine at single or double dosages (up to 80 mumol/kg) delayed hepatic regeneration for at least 8 weeks after partial hepatectomy (PH). This regimen of lasiocarpine and PH had a strong selective influence on the growth of gamma-glutamyltranspeptidase (gamma-GT)-positive hepatocyte nodules in rats previously initiated with diethylnitrosamine. However, both lasiocarpine (up to 80 mumol/kg) and senecionine (up to 160 mumol/kg) were inactive as initiators of gamma-GT-positive nodules in rats exposed to a similar selection regimen consisting of 2-acetylaminofluorene and PH. When lasiocarpine or senecionine was given 12 h after PH, very few nodules were initiated. Lasiocarpine pretreatments reduced the initiating activity of diethylnitrosamine and N-nitrosomethylurea in rats subsequently selected with 2-acetylaminofluorene and PH. Resistant nodules selected with lasiocarpine had the typical resistant nodule phenotype (positive for gamma-GT and epoxide hydrolase) and also lacked pyrrolizidine alkaloid-induced megalocytosis. Lasiocarpine treatment also resulted in small regenerative nodular proliferations of hepatocytes that were distinct from resistant nodules because they were negative for gamma-GT and epoxide hydrolase and unrelated to diethylnitrosamine pretreatments. These studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids can be better explained by their strong selection (promotion) influence on initiated hepatocytes, rather than by their very weak initiating activity.
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PMID:Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine. 286 91

The ingestion of an elevated level (2%) of L-tryptophan (TRP) in a purified diet was investigated to determine whether it would influence the induction of gamma-glutamyltranspeptidase (GGT)-positive foci in the livers of rats exposed to a hepatocarcinogen. Subtotal hepatectomies were performed, and 18 h later, the rats were given injections i.p. of diethylnitrosamine (30 mg/kg). Ten days later, groups of male rats were placed on choline-supplemented (CS), CS + TRP, choline-deficient (CD), or CD + TRP diets for 10 wk. In two separate experiments, the rats fed the CS + TRP diet or the CD diet developed more and larger GGT + foci than did rats fed the CS diet. Rats fed the CD + TRP diet revealed similar changes to those found in rats fed the CD diet. The liver weights of the rats fed the CD or the CD + TRP diet were greater than those of rats fed the CS or the CS + TRP diet. Hepatic GGT activity was somewhat elevated in rats fed the CS + TRP diet and markedly elevated in rats fed the CD or the CD + TRP diet. Hepatic ornithine decarboxylase activity was increased in rats fed the CD + TRP diet. The results suggest that increased dietary tryptophan has a promoting effect on liver carcinogenesis as measured by the induction of GGT + foci in the livers of rats exposed to diethylnitrosamine. A potentiating effect by tryptophan was not observed in the livers of rats fed a CD diet.
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PMID:Influence of dietary tryptophan on the induction of gamma-glutamyltranspeptidase-positive foci in the livers of rats treated with hepatocarcinogen. 286 88

Newborn Swiss-Webster mice were given an intraperitoneal injection of 25 micrograms of dimethylnitrosamine. At weaning they began receiving 0.05% phenobarbital in the drinking water to promote the lesions for the term of the study. Preneoplastic foci and hyperplastic nodules were identified histologically by two markers, resistance to exogenous iron accumulation and an increase in gamma-glutamyltranspeptidase activity. AT 8, 12, and 16 weeks of age, livers of affected male mice exhibited 12, 18, and 12 iron-resistant foci/cm2 and 13, 9, and 9 gamma-glutamyltranspeptidase-positive foci/cm2, respectively (average for median right and right anterior sublobes). Iron-resistant nodules were first observed at 8 weeks; however, gamma-glutamyltranspeptidase-positive nodules were not noted until 12 weeks. In animals that received dimethylnitrosamine but were not placed on phenobarbital, there was an average of 5 foci/cm2 (iron-resistant or gamma-glutamyltranspeptidase-positive) at 12 weeks while no nodules were noted. This model could provide a practical short-term in vivo tool for the detection of early sequential cellular alterations produced by initiators, inhibitors, and promoters of carcinogenesis.
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PMID:Characterization of dimethylnitrosamine-induced focal and nodular lesions in the livers of newborn mice. 286 66

The promotion potential of phenobarbital (PB) and 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) on liver carcinogenesis after initiation with various doses of diethylnitrosamine (DEN) was assessed using an in vivo short term system. Male F344 rats were pretreated with a single intraperitoneal injection of varying doses of DEN (0, 6, 12, 25, 50, 100 or 200 mg/kg body wt), and 2 weeks later were treated with 0.05% PB or 0.06% 3'-Me-DAB for 6 weeks. All animals were subjected to partial hepatectomy 3 weeks after the DEN treatment. Quantitation of gamma-glutamyltranspeptidase-positive (gamma-GT+) foci revealed a DEN dose-dependent response. Magnitude of promotion by PB and more pronounced by 3'-Me-DAB was, in contrast, strongest at the lower doses of DEN. The results suggest that quantitative differences with regard to initiation level may exist, influencing the promotability of initiated cells.
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PMID:Promoting effects of phenobarbital and 3'-methyl-4-dimethylaminoazobenzene on the appearance of gamma-glutamyltranspeptidase positive foci in rat liver pretreated with varying doses of diethylnitrosamine. 286 1

We have investigated the protective effects of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721) on the induction by radiation of altered hepatocyte foci in 150-day-old Sprague-Dawley rats. WR2721 (100 micrograms/g of body weight) was administered to selected groups of neonatal animals 30 min prior to the administration of single doses of ionizing radiation (150 or 300 rads). Two focus phenotypes, described by the histochemical markers gamma-glutamyltranspeptidase and iron exclusion, were quantitated through the use of serial frozen sectioning techniques and computer-assisted image analysis. Although radiation was capable of inducing foci, induction was much more effective in female than in male rats. WR2721, however, reduced the frequencies of radiation-induced foci at both radiation doses, with the protective effect more readily apparent in female animals. The modulation of foci formation by WR2721 in the neonatal rat system suggests that this compound and related aminothiols may be useful probes for examining mechanisms of mutagenesis and carcinogenesis induced by radiation or chemicals.
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PMID:Protective effect of S-2-(3-aminopropylamino)ethylphosphorothioic acid against induction of altered hepatocyte foci in rats treated once with gamma-radiation within one day after birth. 286 3

Biochemical 'markers' of neoplastic cells have been the subject of numerous investigations during the past several decades. Recently, studies from a number of laboratories have demonstrated that a very common biochemical marker for early 'preneoplastic' lesions occurring in several model systems of multistage carcinogenesis, especially hepatocarcinogenesis, is the enzyme, gamma-glutamyltranspeptidase (GGT). Despite the high frequency of this marker, especially in early hepatic lesions, an extensive degree of biochemical heterogeneity is evident when lesions are analyzed for the presence of multiple markers. Such markers have in the past been considered to be relatively stable. However, it is becoming increasingly apparent that environmental factors, drugs, diet, etc. may alter the phenotype of such lesions, especially in respect of GGT activity. Although various model systems have demonstrated different degrees of persistence of biochemically altered focal lesions induced during hepatocarcinogenesis, it is quite likely, but not yet proven, that the potential for the development of each focus remains in the tissue even on disappearance of the histochemical markers. Despite the relatively high frequency of the marker, GGT, in early focal lesions during hepatocarcinogenesis and the generally decreased level of xenobiotic metabolism in these lesions, no single marker, essential or critical for the neoplastic transformation in early or late lesions of hepatocarcinogenesis, has as yet been identified.
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PMID:The significance of selected biochemical markers in the characterization of putative initiated cell populations in rodent liver. 286 27


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