Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: B0001 .4
 471,332 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multifactorial nature of carcinogenesis in man has impelled us to study the effects of various chemicals and conditions in combination. In the present investigation, we examined the effects of low doses of 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) in combination with carbon tetrachloride (CCl4) on the formation of glutathione S-transferase placental form (GST-P)-positive foci in rat liver. Administration of diet containing MeIQx at 0.4, 4 or 40 p.p.m., representing one-thousandth, one-hundredth and one-tenth of the dose proved to induce hepatocellular carcinomas (400 p.p.m.), for 8 or 12 weeks did not induce GST-P-positive foci. However, 40 p.p.m. of MeIQx when co-administered with CCl4 (0.7 ml/kg, s.c. twice a week) induced preneoplastic lesions: 7- and 3-fold increases in the numbers and areas of GST-P positive foci in week 8, and 8- and 6-fold increases respectively in week 12, over those with CCl4 alone. Furthermore, a marked increase in the number of hyperplastic nodules was observed in this group of rats in week 12. No significant increases of GST-P-positive foci were observed at doses of 0.4 or 4 p.p.m. MeIQx in combination with CCl4. Thus, it is predicted that chronic exposure to 40 p.p.m. of MeIQx eventually results in induction of hepatocellular carcinomas in injured rat liver.
Carcinogenesis 1992 May
PMID:Induction of preneoplastic lesions by a low dose of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the livers of rats treated with carbon tetrachloride. 158 92

Exposure to tobacco-specific nitrosamines (TSNA) has been measured in the saliva of 12 users of Sudanese oral snuff (toombak). Using GC coupled to thermal energy analysis, levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were measured before, during and after snuff taking. In addition, two TSNA, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), were detected in the saliva of tobacco chewers for the first time and were confirmed by GC-MS. Nine out of 10 subjects had detectable saliva levels of total TSNA before chewing (0.01-1.0 micrograms/ml) and immediately following chewing (0.1-2.6 micrograms/ml). During dipping, TSNA concentrations reached microgram/ml levels; (range; number of subjects positive) NNN: (0.6-2.1; 12/12), NAT (0.06-0.5; 2/12), NAB (0.05-1.9; 12/12), NNK (0.06-6.7; 11/12), NNAL (0.05-3.3; 11/12) and iso-NNAL (0.07-0.4; 8/12). These saliva TSNA levels, which are 10-100 times the levels previously reported, are consistent with recent observations of unusually high TSNA levels in Sudanese toombak. As several of these TSNA have been shown to be carcinogenic in animals and epidemiological studies have associated human snuff use with tumours of the oral cavity, these findings draw attention to a significant potential public health hazard.
Carcinogenesis 1992 Jun
PMID:Carcinogenic tobacco-specific nitrosamines are present at unusually high levels in the saliva of oral snuff users in Sudan. 160 Jun 2

To investigate an association between colon cancer and obesity during early adulthood--a potentially important period in the etiology of this disease--the authors assembled, by computer linkage, a population-based historical cohort of 52,539 men born between 1913 and 1927 residing in Hawaii (USA), for whom weight and height had been recorded in 1942-43 and 1972. Linkage of this cohort to the Hawaii Tumor Registry resulted in the identification of 737 incident cases of colorectal cancer for 1972-86. An average of 3.8 cancer-free controls were matched to each case on month and year of birth and ethnicity of the parents. A case-control analysis in each anatomic subsite of the large bowel revealed that both early and middle-age body mass increased the risk of sigmoid cancer in men in a dose-dependent fashion. The odds ratios (OR) for sigmoid cancer for the highest compared with the lowest tertiles of Quetelet index were: 2.1 (95 percent confidence interval [CI] = 1.4-3.2) and 1.7 (CI = 1.1-2.5), at ages 15-29 and in prediagnostic years, respectively. These associations were additive and independent of socioeconomic status. Men who were above the median Quetelet index in 1942 and 1972 had an OR of 2.7 (CI = 1.8-4.0), compared with those who were below the median in both periods. This study provides further evidence for an association of obesity with colon cancer in men and suggests that this association is limited to the sigmoid colon and may be related to both early and late events of colon carcinogenesis.
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PMID:Obesity in youth and middle age and risk of colorectal cancer in men. 161 22

Experimental and epidemiologic investigations in alcoholic and nonalcoholic populations have suggested a role of alcohol in lung carcinogenesis. The association between alcohol consumption and lung cancer was investigated among 280 White males with histologically confirmed, primary lung cancer and 564 White male controls, participants in the Western New York Diet Study (United States). Among heavy smokers (over 40 pack-years), total alcohol consumption was associated with an increased risk of lung cancer with adjustment for age, years of education, pack-years of cigarette smoking, and intake of carotenoids and fat. In this group, the odds ratio for drinkers of more than 24 drinks per month was 1.6 compared with those who drank less. Drinkers of more than 12 beers per month were 1.6 times more likely to develop lung cancer than nondrinkers of beer after controlling for age, years of education, and cigarette smoking (95 percent confidence interval = 1.0-2.4, P for trend = 0.003). Occupational and dietary factors did not seem to explain these findings. Although cigarette smoking is the major cause of lung cancer, the role of alcohol, independent or in interaction with cigarette smoking, deserves further investigation.
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PMID:Alcohol consumption and lung cancer in white males. 1151 66

Diethylstilbestrol (DES) or catecholestrogens are metabolized by microsomal enzymes to quinones, DES Q or catecholestrogen quinones, respectively, which have been shown to bind covalently to DNA and to undergo redox cycling. The isoforms of cytochrome P450 catalyzing this oxidation of estrogens to genotoxic intermediates were not known and have been identified in this study by (a) using microsomes of rats treated with various inducers of cytochrome P450; (b) using purified cytochrome P450 isoforms; and (c) examining the peroxide cofactor concentrations necessary for this oxidation by microsomes or pure isoenzymes. The highest rate of oxidation of DES to DES Q was obtained using beta-naphthoflavone-induced microsomes (14.0 nmol DES Q/mg protein/min) or cytochrome P450 IA1 (6.4 pmol DES Q/min/pmol P450). Isosafrole-induced microsomes or cytochrome P450 IA2 oxidized DES to quinone at one-third or one-fifth of that rate, respectively. Low or negligible rates of oxidation were measured when oxidations were catalyzed by microsomal rat liver enzymes induced by phenobarbital, ethanol, or pregnenolone-16 alpha-carbonitrile or by pure cytochromes P450 IIB1, IIB4, IIC3, IIC6, IIE1, IIE2, IIG1, or IIIA6. Cytochrome P450 IA1 also catalyzed the oxidation of 2- or 4-hydroxyestradiol to their corresponding quinones. The beta-naphthoflavone-induced microsomes and cytochrome P450 IA1 had the highest "affinity" for cumene hydroperoxide cofactor (Km = 77 microM). Cofactor concentrations above 250 microM resulted in decreased rates of oxidation. The other cytochrome P450 isoforms required much higher cofactor concentrations and were not inactivated at high cofactor concentrations. The data demonstrate that beta-naphthoflavone-inducible cytochrome P450 IA family enzymes catalyze most efficiently the oxidation of estrogenic hydroquinones to corresponding quinones. This oxidation may represent a detoxification pathway to keep organic hydroperoxides at minimal concentrations. The resulting quinone metabolites may be detoxified by other pathways. However, in cells with decreased detoxifying enzyme activities, quinones metabolites may accumulate and initiate carcinogenesis or cell death by covalent arylation of DNA or proteins.
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PMID:Catalysis of the oxidation of steroid and stilbene estrogens to estrogen quinone metabolites by the beta-naphthoflavone-inducible cytochrome P450 IA family. 163 37

Chlorophyllin (CHL), a copper/sodium salt of chlorophyll used in the treatment of geriatric patients, is an anti-mutagen that has been demonstrated to inhibit carcinogen--DNA binding in vivo. To study the mechanism of inhibition, the microsomal metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and the kinetics of IQ--DNA binding were investigated in the presence and absence of CHL. In time-course studies, CHL produced greater than 80% inhibition of IQ--DNA binding and blocked the metabolism of IQ, such that 80% of the initial dose of carcinogen was recovered unmetabolized from the incubations after 1 h. Kinetic constants were determined for the in vitro DNA binding reaction, with the reaction rate measured as 'pmol IQ bound/mg DNA/min/mg microsomal protein'. Without altering V(max), the Km of the IQ--DNA binding reaction was increased by CHL, and the replot of Km/V(max) versus CHL concentration yielded a straight line with an inhibitor constant of 58.3 microM CHL. Spectrophotometric studies provided evidence in vitro for the formation of a non-covalent complex between CHL and IQ. The CHL--IQ complex had a stoichiometric ratio of 2:1 (mole ratio method) and an apparent dissociation constant from the Benesi-Hilderbrand plot of 1.41 x 10(-4)M at pH 7.4. These results are discussed in the context of a CHL inhibitory mechanism involving enzyme inhibition and molecular complex formation.
Carcinogenesis 1992 Jul
PMID:Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA binding by chlorophyllin: studies of enzyme inhibition and molecular complex formation. 163 77

Consumption of alcoholic beverages has been identified as a major cause of oesophageal cancer in industrialized countries, with an exceptionally high risk associated with apple-based liquors (calvados). In the present study, we have determined the dose--activity relationship of the effects of coincident ethanol on the formation of O6-methyldeoxyguanosine (O6-MEdG) by the oesophageal carcinogen N-nitrosomethylbenzylamine (NMBzA). Male Fischer 344 rats received a single intragastric dose of NMBzA (2.5 mg/kg body wt; 7.4 ml/kg body wt) in tap water containing 0-20% ethanol (v/v). Survival time was 3 h. In controls, concentrations of O6-MEdG were similar in oesophagus, lung and liver (11-14.9 mumol/mol dG). In oesophagus, coincident ethanol increased levels of O6-MEdG from 15.2 mumol/mol (0.1% ethanol) to 46.0 mumol/mol (20%). This increase was dose dependent for 1-20% ethanol; however, low doses produced a larger effect per gram of ethanol than higher doses. In lung, concentrations of O6-MEdG increased from 11 mumol/mol (0.1%) to a plateau value of 24 mumol/mol (greater than or equal to 5%). In nasal mucosa, an increase in O6-MEdG from 3.9 mumol/mol (controls) to 30.7 mumol/mol was observed with 4% ethanol. Effects of ethanol on hepatic DNA methylation were statistically non-significant. Modulation of NMBzA bioactivation by various alcoholic beverages (adjusted to 4% ethanol) was also investigated. Increases in oesophageal O6-MEdG were similar (+50% to +116%) with pear brandy, rice wine (sake), farm-made calvados, gin, Scotch whisky, white wine, Pilsner beer and aqueous ethanol. Significantly higher increases were elicited by commercially distilled calvados (+125%) and red burgundy (+162%). In contrast to its effects at an ethanol content of 4%, farm-made calvados diluted to 20% ethanol produced significantly higher (+200%) increases in oesophageal DNA methylation than aqueous ethanol (+148%). Our results show that ethanol is an effective modulator of nitrosamine bioactivation in vivo at intake levels equivalent to moderate social drinking, and that some alcoholic beverages contain congeners that amplify the effects of ethanol, suggesting that modulation of nitrosamine metabolism by acute ethanol may play a role in the etiology of human cancer.
Carcinogenesis 1992 Jul
PMID:Effects of ethanol and various alcoholic beverages on the formation of O6-methyldeoxyguanosine from concurrently administered N-nitrosomethylbenzylamine in rats: a dose-response study. 163 83

Deviations in the pattern of soluble proteins from chemically induced primary rat hepatomas and from transformed, tumorigenic liver cell lines were determined by high resolution two-dimensional gel electrophoresis (2DE). As compared with the protein pattern of normal rat liver with approximately 1300 protein spots visible in silver-stained gels, quantitative and qualitative alterations were found in hepatomas including neoexpression of glutathione-S-transferase P, as described earlier. After correction for proliferation-related changes by comparison with gels of cells from regenerating rat liver, 30 protein variants remained, which were identically up- (n = 6) or down-regulated (n = 18) or were detected as new spots (n = 6) in primary hepatomas and transformed tumorigenic liver cell lines which are devoid of contaminating nonparenchymal cells. Seven of these variants showed a reduced expression in short-term cultured liver cells indicating dedifferentiation processes in the transformed state. Several hepatoma- and transformation-associated variants were found in clusters of similar mol. wt and/or pI, among them a complex of eight protein variants at approximately 33-35.5 kDa and a pI of approximately 6.6-7.4. Spots of this cluster show considerable changes between the investigated experimental groups and might be suited for being studied at the level of posttranslational modification during carcinogenesis.
Carcinogenesis 1992 Jul
PMID:Variant protein patterns in hepatomas and transformed liver cell lines as determined by high resolution two-dimensional gel electrophoresis (2DE). 163 84

A non-transformed human fibroblast strain, GM11, established from the skin of a therapeutically aborted fetus, has been reported to exhibit the Mer- phenotype, i.e. inability to support the growth of adenovirus 5 damaged with 1-methyl-3-nitro-1-nitrosoguanidine. In the present study we determined (i) loss of colony-forming ability and frequency of mutants resistant to 6-thioguanine (6TG) on exposure to the SN1 alkylating agent methylnitrosourea (MNU) and (ii) amount of O6-methylguanine-DNA methyltransferase (MGMT), the protein responsible for repairing O6-methylguanine (O6mG) produced by MNU, in GM11 cells compared to GM10, a Mer+ human fetal fibroblast strain. Irrespective of in vitro culture age, GM10 cells responded normally to the cytotoxic action of the alkylating agent, i.e. their clonogenic survival curves exhibited a shoulder at low MNU concentrations (less than or equal to 0.4 mM) and a D10 (dose reducing survival to 10%) of approximately 1.4 mM. By contrast, no shoulder was observed on the survival curves of GM11 cells and their D10 values decreased from approximately 0.6 mM at passage 4 to 0.1 mM at passage 27. In GM10 (Mer+) cells, unlike the biphasic dose response seen for cell killing, the frequency of 6TG-resistant mutants increased as a linear function of chemical concentration delivered (range 0.05-1.2 mM); the induced mutation frequency in these cells (passage 16-20) was equal to 220 x 10(-6)/mM MNU, a yield some 5-fold greater than that reported by others for non-fetal human fibroblasts. GM11 cells proved to be only approximately 1.5 times more mutable by MNU than GM10 cells at late passage, and the susceptibility of the former strain to MNU-induced mutations did not change significantly as a function of culture age (i.e. 316 x 10(-6) and 326 x 10(-6) mutants/mM MNU at passages 4 and 16-20 respectively). The GM10 strain contained approximately 75,000 MGMT molecules/cell at all passages (4-20) examined, whereas the GM11 strain harbored deficient amounts of the protein (approximately 22,500 molecules/cell) at the lowest passage available (4), and this residual activity decreased precipituously to undetectable amounts by passage 16. Together, these data demonstrate that in the two human fetal strains examined the constitutive level of cellular MGMT activity correlates much better with resistance to reproductive inactivation than with mutagenesis by MNU, implying that inefficient repair of O6meG lesions impacts more severely on cell lethality than on mutation induction in at least some biological systems.
Carcinogenesis 1992 Jul
PMID:Cytotoxic and mutagenic effects of methylnitrosourea in two human fetal fibroblast strains differing in O6-methylguanine-DNA methyltransferase activity. 163 85

Results of experiments in our laboratory have shown that benzene is metabolized by animals in part to an intermediate that binds to cysteine groups in hemoglobin to form the adduct S-phenylcysteine (SPC). These results suggested that SPC in hemoglobin may be an effective biological marker for exposure to benzene. However, we could not detect SPC in the globin of humans occupationally exposed to benzene concentrations as high as 28 p.p.m. for 8 h/day, 5 days/week. As another approach, we examined the binding of benzene to cysteine groups of a different blood protein, albumin. To facilitate the process, a new method for the precipitative isolation of albumin from plasma was also developed. The isolated albumin was analyzed for SPC by isotope dilution GC-MS. We used this approach to measure SPC in the albumin of F344/N rats exposed by gavage to 0-10,000 mumol/kg benzene. Amounts of albumin-associated SPC increased as a function of dose, followed by a leveling off in the amount of SPC seen at doses greater than 1000 mumol/kg. Levels of SPC were measured in humans occupationally exposed to average concentrations of 0, 4.4, 8.4 and 23 p.p.m. benzene 8 h/day, 5 days/week. Of nine controls, seven had levels of SPC below the limit of detection (0.1 pmol SPC/mg albumin). SPC increased in the exposed groups linearly, giving a statistically significant slope (P less than 0.001) of 0.044 +/- 0.008 pmol/mg albumin/p.p.m. with an intercept of 0.135 +/- 0.095 pmol/mg albumin. From this study, we conclude that SPC in albumin may prove useful as a biomarker for benzene exposure.
Carcinogenesis 1992 Jul
PMID:Biological markers of exposure to benzene: S-phenylcysteine in albumin. 163 89


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