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

Hepatocellular carcinomas from rats of different strains, subjected to a variety of carcinogenic treatment regimens in different laboratories (initiation by diethylnitrosamine or dimethylhydrazine, promotion by phenobarbital, 2-acetylaminofluorene, nafenopin, orotic acid or deoxycholic acid, growth stimulation by partial hepatectomy or necrogenic CCl4 treatment), were all found to be predominantly diploid by flow cytometric analysis, in contrast to normal liver tissue in which polyploid nuclei were predominant. A switch from polyploidization to diploid growth would thus seem to be a common property of malignant liver tumours. Benign neoplastic liver nodules were likewise predominantly diploid, with the exception of nodules induced by long-term deoxycholic acid treatment in Fischer rats. In addition to containing a majority of polyploid cells, the latter nodules failed to progress to the carcinoma stage.
Carcinogenesis 1991 Feb
PMID:Diploid growth pattern of hepatocellular tumours induced by various carcinogenic treatments. 184 21

The cytochrome P450-dependent reduction of Cr(VI) using reconstituted phospholipid vesicles containing purified preparation of various forms of rabbit and rat liver microsomal cytochrome P450 has been investigated. The alcohol-induced form of the rat, P450IIE1, was the most efficient enzyme, 7.2 +/- 0.40 nmol Cr/nmol P450/min, whereas the corresponding rates for rat P450IA1, rat IIB1, rabbit IIB4, rabbit IA2 and rabbit IIE1 were 1.7 +/- 0.09, 2.5 +/- 0.08, 1.6 +/- 0.08, 2.5 +/- 0.15 and 1.6 +/- 0.08 nmol Cr/nmol P450/min respectively. NADPH-cytochrome P450 reductase had Cr(VI) reductase activity which was dependent on enzyme concentration. Below 0.15 nmol P450 reductase/ml the sp. act. was low and constant, while at a higher concentration the activity was markedly dependent upon the amount of enzyme present. In a quantitative binding assay it was shown that binding of [51Cr]Cr(VI) to the catalytic enzymes was proportional to the enzyme concentration up to 0.8 nmol P450/ml, which caused binding of 70% of the total radioactivity. Analysis by SDS-PAGE and autoradiography exhibited binding to the individual catalytic proteins of [51Cr]Cr. EDTA treatment removed the radioactivity from the bands matching P450 and P450 reductase, indicating that Cr(III) is bound to the proteins. The reducing activity of both P450 and P450 reductase was potently inhibited by oxygen. The inhibitory effect of oxygen is not due to reoxidation of the reduced Cr and redox cycling. Rat P450IA1 ethoxycoumarin O deethylase activity was inhibited after preincubation with chromate (CrO4(2-). The P450 reductase inhibitor 2'-AMP stimulated the anaerobic P450 reductase dependent Cr(VI) reductase rate approximately 2-fold. Both CO and CCl4 inhibited the different P450 enzymes to various extents. With rabbit P450IIE1 CCl4 stimulated the Cr(VI) reduction approximately 4-fold, whereas the activity of the other enzymes was inhibited when the reconstituted system was incubated with CrO4(2-) and CCl4 prior to NADPH addition. Neither CO nor CCl4 affected the Cr(VI) reducing activity of the P450 reductase. The difference in CrO4(2-) reducing activity of the P450 enzymes and binding to the enzymes may be important for in vivo endoplasmic catalytic metabolism of CrO4(2-).
Carcinogenesis 1991 May
PMID:Reductive metabolism and protein binding of chromium(VI) by P450 protein enzymes. 190 91

Experiments were designed to investigate the expression of three cell-cycle-dependent proto-oncogenes in response to two different types of proliferative stimuli: compensatory cell proliferation after partial hepatectomy (PH) or CCl4 and liver hyperplasia induced by the mitogens ethylene dibromide (EDB) and cyproterone acetate (CPA). Steady-state levels of messenger RNAs for c-fos and c-myc were found to be elevated after PH or CCl4 with a maximum increase between 0.5 and 2 h for c-fos and at 2-3 h for c-myc and a rapid decline after 3 h. However, when liver cell proliferation was induced by mitogens, no increase in the expression of c-fos mRNA was observed with both EDB or CPA during the first 24 h. In addition, elevated expression of c-myc was found only in liver hyperplasia induced by EDB, but not with CPA. While the expression of c-myc mRNA and c-fos mRNA was different in the two types of proliferative stimuli, that of c-Ha-ras and c-Ki-ras was similar in all the experimental groups. Cell proliferation monitored by means of incorporation of labelled thymidine into DNA or mitotic index at 24 h following PH, EDB and CPA occurred at a similar extent in all the experimental groups. Our data indicate that the transient and sequential expression of cell-cycle-related genes may vary in response to proliferative stimuli of different nature and suggest that increased expression of cell-cycle-related genes may not be a necessary prerequisite for the entry of the cells into the cell cycle.
Carcinogenesis 1990 May
PMID:Liver hyperplasia is not necessarily associated with increased expression of c-fos and c-myc mRNA. 213 17

Machine oils are widely used in metal processing and many workers are exposed to oil mists in the work environment. Some investigators have pointed out such health hazards due to prolonged exposure to oil mist as respiratory disorders, dermatitis, and possible carcinogenesis. In Japan, a permissible limit of oil mists of 3 mg/m3 was recommended in 1977 by the Japan Association of Industrial Health (JAIH) mainly based on the hazardous effects on the respiratory system. After this recommendation was made, only a few studies have been made on the measurement of oil mists and on the health effects in machine workers to determine whether the permissible limit is justifiable or not. In the present study, the levels of oil mists in the air of machine workshops were measured together with personal exposure levels by personal samplers. Oil mists were collected by a sampler head with 2 stages which enabled differentiation of distribution of particulates between larger than 10 microns and 2-10 microns in size. Oil components collected on the stainless steel stages were washed out by sonication in CCl4 solution and measured by an oil meter with infra-red spectrometry against a standard solution of heavy oil class B according to procedures reported elsewhere by the authors. Questionnaire surveys were also conducted on 308 male machine workers composed of 221 workers exposed to oil mists and 87 nonexposed controls. The questions were composed of five items about air quality in the work environment and 18 subjective symptoms during work and daily lives. The symptoms included nasopharyngeal, muco-dermal, gastrointestinal and neuro-muscular symptoms. Statistical analysis was made by the Manthel-Haenszel method for a comparison of "yes" rates of complaints between the exposed and the non-exposed by adjusting the underlying confounding factor of age distribution. 1. The levels of oil mists measured here ranged from 94 to 813 micrograms/m3 in the ambient air and from 107 to 483 micrograms/m3 of personal exposure. There was no obvious difference between the level in the ambient air and that of personal exposure. All these measured levels were under the permissible limit (3 mg/m3) recommended by JAIH in 1977. 2. The observed distribution of particulate size of oil mists from 2 to 10 microns referred to as respirable size was 32.8 +/- 16.1% generated from the grinding machines using water-soluble type of machine oils and 50.0 +/- 12.4% from those using insoluble type.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Measurement of oil mists by a portable sampler and subjective symptoms among machine workers: a field investigation of machine workshops]. 227 88

In order to investigate whether the stimulation of liver DNA synthesis might be used to detect one class of hepatic tumor promoters, the incorporation of orally administered radiolabelled thymidine into liver DNA was determined in rats and mice 24 h after a single oral gavage of test compounds at various dose levels. Three DNA-binding hepatocarcinogens, aflatoxin B1, benzidine and carbon tetrachloride, did not stimulate but rather inhibited DNA synthesis (not for CCl4). Four hepatic tumor promoters, clofibrate, DDT, phenobarbital and thioacetamide, gave rise to a stimulation in a dose-dependent manner. Single oral doses between 0.02 and 0.3 mmol/kg were required to double the level of thymidine incorporation into liver DNA (= doubling dose, DD). Differences between species or sex as observed in long-term carcinogenicity studies were reflected by a different stimulation of liver DNA synthesis. In agreement with the bioassay data, aldrin was positive only in male mice (DD = 0.007 mmol/kg) but not in male rats of female mice. 2,3,7,8-TCDD was positive in male mice (DD = 10(-6) mmol/kg) and in female rats (DD = 2 X 10(-6) mmol/kg) but not in male rats. The assay was also able to distinguish between structural isomers with different carcinogenicities. [alpha]Hexachlorocyclohexane stimulated liver DNA synthesis with a doubling dose of about 0.2 mmol/kg in male rats whereas the [gamma]-isomer was ineffective even at 1 mmol/kg. So far, only one result was inconsistent with carcinogenicity bioassay data. The different carcinogenicity of di(2-ethylhexyl)adipate (negative in rats) and di(2-ethylhexyl)phthalate (positive) was not detectable. Both plasticizers were positive in this short-term system with DD's of 0.7 mmol/kg for DEHA and 0.5 mmol/kg for DEHP. The proposed assay is discussed as an attempt to devise short-term assays for carcinogens not detected by the routine genotoxicity test systems.
Carcinogenesis 1987 Oct
PMID:Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters. 244 63

A rat liver gap junction (GJ) cDNA probe that detects mRNA encoding the 32 Kd GJ-protein (connexin 32) was employed to study GJ-protein gene expression in rat liver tumors induced by a single exposure to diethylnitrosamine (DEN) followed by exposure to 2-acetylaminofluorene (AAF)/CCl4/AAF or induced by systemic administration of N-ethyl-N-hydroxyethylnitrosamine (EHEN). All carcinomas generated by these carcinogens showed markedly reduced levels of GJ-protein mRNA. This may indicate that GJ-protein levels and gap-junctional intercellular communication (GJIC) capacity are also severely compromised. Moreover, all hyperplastic nodules also showed a reduced level of GJ-protein mRNA. Taken together with our earlier finding that the liver tumor promoter phenobarbital inhibits GJ-protein gene expression, these results suggest that deranged GJIC is a relatively early event in liver multistage carcinogenesis. A range of other cDNA probes was also used to characterize gene expression in the DEN-induced tumors. Induction of expression was seen for glutathione S-transferase (placental form) (GST-P), gamma-glutamyltranspeptidase (GGT), and c-raf but not for c-Ha-ras or c-myc.
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PMID:Changes in gap junction protein (connexin 32) gene expression during rat liver carcinogenesis. 255 87

Our earlier studies have revealed that direct hyperplasia induced by liver mitogens such as lead nitrate, ethylene dibromide, nafenopin and cyproterone acetate, unlike compensatory cell proliferation induced by partial hepatectomy and CCl4, does not support the formation of enzyme-altered islands induced by chemical carcinogens in the liver. In the previous studies carcinogens were given at the peak of DNA synthesis induced by the liver mitogens. If the mitogens have altered the sensitive phase of the hepatocyte to the carcinogenic attack, administering the carcinogen at one time point following the mitogenic stimulus might have missed the sensitive phase. In order to overcome this possibility in the present study male Wistar rats weighing 200-250 g were given N-methyl-N-nitrosourea (MNU; 60 mg/kg, i.p.) at three points representing G1, S and G2/M phases of the cell cycle following different types of liver cell proliferative stimuli. In another experiment MNU (60 mg/kg, i.p.) and diethylnitrosamine (15 mg/kg, i.p.) were given prior to the administration of proliferative stimuli. The initiated hepatocytes were also assayed following promotion by two different promoting regimens, namely phenobarbital and the resistant-hepatocyte model. Further, the initiated hepatocytes were monitored not only by using the appearance of islands of enzyme-altered hepatocytes but also using the incidence of hepatocellular carcinoma. The results of this study clearly revealed that irrespective of the protocol used, only the compensatory liver cell proliferation but not the mitogen-induced direct hyperplasia supported the formation and the growth of enzyme-altered islands in the liver induced by chemical carcinogens.
Carcinogenesis 1989 May
PMID:Further evidence that mitogen-induced cell proliferation does not support the formation of enzyme-altered islands in rat liver by carcinogens. 256 71

To test the validity of the hypothesis that hypomethylation of DNA plays an important role in the initiation of carcinogenic process, 5-azacytidine (5-AzC) (10 mg/kg), an inhibitor of DNA methylation, was given to rats during the phase of repair synthesis induced by the three carcinogens, benzo[a]-pyrene (200 mg/kg), N-methyl-N-nitrosourea (60 mg/kg) and 1,2-dimethylhydrazine (1,2-DMH) (100 mg/kg). The initiated hepatocytes in the liver were assayed as the gamma-glutamyltransferase (gamma-GT) positive foci formed following a 2-week selection regimen consisting of dietary 0.02% 2-acetylaminofluorene coupled with a necrogenic dose of CCl4. The results obtained indicate that with all three carcinogens, administration of 5-AzC during repair synthesis increased the incidence of initiated hepatocytes, for example 10-20 foci/cm2 in 5-AzC and carcinogen-treated rats compared with 3-5 foci/cm2 in rats treated with carcinogen only. Administration of [3H]-5-azadeoxycytidine during the repair synthesis induced by 1,2-DMH further showed that 0.019 mol % of cytosine residues in DNA were substituted by the analogue, indicating that incorporation of 5-AzC occurs during repair synthesis. In the absence of the carcinogen, 5-AzC given after a two thirds partial hepatectomy, when its incorporation should be maximum, failed to induce any gamma-GT positive foci. The results suggest that hypomethylation of DNA per se may not be sufficient for initiation. Perhaps two events might be necessary for initiation, the first caused by the carcinogen and a second involving hypomethylation of DNA.
Carcinogenesis 1985 Jan
PMID:5-azacytidine potentiates initiation induced by carcinogens in rat liver. 257 34

CCl4 has been reported to be a liver carcinogen for several mice strains, for Syrian Golden hamsters, but not for Sprague-Dawley rats. CCl4 is an experimental carcinogen for which no convincing evidence of mutagenicity is available despite the fact that CCl4 reactive metabolites bind covalently to liver DNA. Here we describe studies on the relationship between the intensities of the covalent binding (CB) of CCl4 reactive metabolites to liver DNA and nuclear proteins either in vivo or in vitro after activation to reactive metabolites by nuclear preparations, considering the known susceptibility of the C3H mice, Syrian Golden hamsters and Sprague-Dawley rats to CCl4. There was no correlation between the intensity of CCl4 carcinogenic effects on the liver and CB of CCl4 reactive metabolites to total DNA either in vitro or in vivo. A good correlation between carcinogenicity and CB to total nuclear proteins (in vivo or in vitro was found. Nuclear protein fractionation studies revealed CB of CCl4 reactive metabolites to both histone and non-histone proteins when nuclear preparations activated CCl4 either in the presence or absence of NADPH. Acidic and residual nuclear proteins were the favorite targets of the interaction with CCl4 reactive metabolites. A good correlation between CB to these nuclear protein fractions and CCl4 carcinogenicity in the three species was found.
Carcinogenesis 1989 Feb
PMID:Species differences in the interaction between CCl4 reactive metabolites and liver DNA or nuclear protein fractions. 264 84

The role of sulfation in the covalent binding of [ring-3H]-N-hydroxy-2-acetylaminofluorene (N-OH-AAF) in rat liver containing gamma-glutamyltranspeptidase-positive (GGT+) foci was studied in vivo by autoradiography. GGT+ foci were induced by initiation with diethylnitrosamine, followed by a selection protocol consisting of a 2-week exposure to 2-aminofluorene in the drinking water and a single administration of CCl4. Both surrounding ('normal') liver tissue and, to a lesser extent, GGT+ foci covalently bound N-OH-AAF, administered 10 days after selection. The sulfation inhibitor, pentachlorophenol (PCP), reduced the covalent binding of N-OH-AAF in cells surrounding the foci. However, PCP had no effect on binding of radiolabel in GGT+ foci. Thus, reduced sulfotransferase activity may contribute to the resistance of GGT+ preneoplastic lesions to carcinogen cytotoxicity. The results suggest also, that cells in GGT+ foci are able to bind N-OH-AAF covalently by a sulfotransferase-independent pathway.
Carcinogenesis 1987 Apr
PMID:Autoradiographic studies on in vivo covalent binding of N-hydroxy-2-acetylaminofluorene in rat liver containing gamma-glutamyltranspeptidase-positive foci. The effect of the sulfation-inhibitor pentachlorophenol. 288 32


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