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)

Male and female rats were treated according to the resistant hepatocyte model, i.e. initiation with diethylnitrosamine (DEN) and selection/promotion with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). Non-initiated controls were either treated with 2-AAF/PH or with PH only. Initiated male controls, where PH was performed, were also included. In livers obtained at PH marked effects of treatment with DEN and/or 2-AAF on several cytochrome P450-mediated microsomal reactions towards steroid and xenobiotic substrates were observed. Hepatic N,O-sulfation of N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) was decreased in rats of both sexes in response to 2-AAF treatment at the time of PH. Microsomes prepared from early male nodules, collected 39 days after initiation, exhibited levels of cytochrome P450 similar to that in liver from non-initiated male rats treated with 2-AAF/PH. The microsomal content of cytochrome P450 in nodules from both male and female rats, at 8 and 11 months after the start of the experiment respectively, was lower than that of the surrounding liver. No differences in the metabolism of 4-androstene-3,17-dione (androstenedione) were observed in early male nodules compared with 2-AAF/PH-treated controls. Eight months after initiation several sex differentiated hydroxylations of androstenedione (male greater than female) were lower in nodules than in surrounding and control liver from male rats. Female nodules obtained 11 months post-initiation exhibited a markedly lower capacity for 5 alpha-reduction of androstenedione (male greater than female) than the surrounding liver, whereas no significant differences were observed with respect to the different hydroxylation pathways. N,O-Sulfation of N-OH-2-AAF was the only reaction that was markedly decreased in preparations from early male nodules, compared with livers from non-initiated 2-AAF/PH-treated males. Also in late male nodules the sulfotransferase activity was lower than in the surrounding liver. At 11 months, N,O-sulfation in preparations from female rat liver did not reach the detection level. In conclusion, several enzyme activities are markedly less sex differentiated in nodular tissue from male and female rats than in surrounding tissue or in different kinds of control rat liver. These findings indicate that hepatocyte nodules are to some extent withdrawn from the normal endocrine regulation of rat liver.
Carcinogenesis 1990 Jul
PMID:Loss of sexual differentiation of metabolism of steroids and xenobiotics in nodular hepatic tissue from male and female Wistar rats treated according to the resistant hepatocyte model. 237 66

In order to compare the interactions of procarcinogens with mammary cells from humans and rats, a uniform set of mediated mutagenesis assays has been established. In these assays, species-specific mammary epithelial cells activate procarcinogens, and specific locus mutations are quantitated in cocultured V-79 cells. Mutations were induced in the rat mammary cell coculture system exposed to 7,12-dimethylbenz(a)anthracene but not benzo(a)pyrene. In contrast, in the human mammary cell coculture system benzo(a)pyrene was much more effective than 7,12-dimethylbenz(a)anthracene in the induction of mutations. These results suggest caution in extrapolating carcinogenesis data between rodents and humans. They also suggest that the relationship between the ubiquitous environmental xenobiotic benzo(a)pyrene and the etiology of human breast cancer requires further exploration.
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PMID:Interspecies comparison of human and rat mammary epithelial cell-mediated mutagenesis by polycyclic aromatic hydrocarbons. 242 69

Studies with regenerating liver and hepatocyte cultures have shown that the alpha-1 adrenergic receptor (A1AR) is involved in the early events which transmit a mitogenic signal to hepatocytes after 2/3 partial hepatectomy. In this study, we investigated the role of A1AR in DNA synthesis associated with the augmentative hyperplasia stimulated by the xenobiotic hepatic tumor promoters phenobarbital (PB) and alpha-hexachlorocyclohexane (alpha-HCH), and the peroxisome proliferator ciprofibrate. Male F344 rats were treated with each of the three xenobiotics to stimulate hepatic DNA synthesis. When either phenobarbital or alpha-HCH administration was preceded and accompanied by the A1AR antagonist prazosin, DNA synthesis was significantly inhibited, as measured by [3H]thymidine incorporation or 5-bromo-2'-deoxyuridine (BrdU) nuclear labeling index. There was no inhibition of DNA synthesis by prazosin in the ciprofibrate treated group. The inhibition of hepatic DNA synthesis by prazosin was accompanied by non-significant changes in the number of alpha-1 binding sites in the PB and alpha-HCH treated groups, but a significantly reduced number of alpha-1 binding sites in the ciprofibrate treated group. These studies suggest that A1AR is involved in generating the mitogenic signal leading to hepatic DNA synthesis induced by xenobiotic hepatic tumor promoters phenobarbital and alpha-HCH. A1AR is not involved in the mitogenic pathway generated by the peroxisome proliferator ciprofibrate.
Carcinogenesis 1989 Jan
PMID:Blockade of alpha-1 adrenergic receptor inhibits hepatic DNA synthesis stimulated by tumor promoters. 246 15

The effects of dietary Brussels sprouts and indole-3-carbinol (I3C) on xenobiotic-metabolizing enzyme activities and hepatic aflatoxin B1 (AFB1)-DNA binding were determined in rats. Animals were dosed intraperitoneally (i.p.) or intragastrically (i.g.) with [3H]AFB1 and killed 2 (i.p.) or 3 (i.g.) h later. Brussels sprouts caused a significant (P less than 0.01) 50-60% decrease in hepatic AFB1-DNA binding, and increased hepatic and intestinal glutathione S-transferase (GST) activities. Hepatic mono-oxygenase (AHH and ECD) activities were not altered in sprouts-fed rats, but greater than 2-fold increases in intestinal AHH and ECD activities were found. Although I3C increased intestinal AHH and ECD activities similarly to Brussels sprouts, I3C did not significantly decrease AFB1 binding, nor did it increase hepatic or intestinal GST activity. Route of administration did not alter the percentage inhibition of binding in comparison to control rats in either treatment group, suggesting that the small intestine may not play a significant role in the metabolism of AFB1. In a second experiment, rats were dosed either i.p. or i.g. with [3H]AFB1 and killed 2, 6, 12, 24 or 48 h later. Hepatic AFB1-DNA binding and tissue radioactivity levels were determined. Brussels sprouts once again significantly (P less than 0.001) decreased hepatic AFB1-DNA binding. Route of administration of the carcinogen did not affect DNA binding over time in sprouts-fed animals, confirming our previous results.
Carcinogenesis 1989 Apr
PMID:Effect of diet and route of administration on the DNA binding of aflatoxin B1 in the rat. 270 10

Alkylation of DNA by xenobiotic agents, or their electrophilic metabolites, is believed to be the major initiating process that may result ultimately in carcinogenesis. The study of hemoglobin alkylated in vivo by chemical carcinogens has previously been proposed as an indicator for DNA alkylation. Xenobiotically modified proteins, however, are not readily amenable to conventional methods for amino acid sequencing. Tandem mass spectrometry allows unambiguous structural elucidation of chemically modified proteins. Styrene is a widely used chemical in the plastics industry and its major metabolite, styrene 7,8-oxide, is both mutagenic and carcinogenic in rodents. Human hemoglobin was modified in vitro with styrene 7,8-oxide and digested with trypsin. Tryptic peptides from unmodified hemoglobin were isolated by high performance liquid chromatography, and their molecular weights were determined by liquid secondary ion mass spectrometry. This allowed confirmation of the known sequence of the protein and provided a reference for the identification of modified peptides. High performance tandem mass spectrometry of modified peptides allowed unambiguous assignment of specific residues modified. The externally accessible histidines were found to be the dominant sites for alkylation at high modification levels of the protein.
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PMID:Characterization of structural xenobiotic modifications in proteins by high sensitivity tandem mass spectrometry. Human hemoglobin treated in vitro with styrene 7,8-oxide. 279 39

Aerobic oxidation of 3-hydroxyamino-1-methyl-5H-pyrido-[4,3-b]indole [Trp-P-2(NHOH)] in neutral aqueous solution was greatly accelerated by copper-zinc superoxide dismutase (SOD). The major product in this SOD-mediated reaction was identified as 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2(NO)]. This conversion was accompanied by a decrease of the mutagenicity of the mixture, as monitored by the direct-acting mutagenicity on Salmonella typhimurium TA98; a rapid change to approximately 1/3 of the original mutagenicity was followed by no further decrease of the activity. In contrast, in the spontaneous aerobic oxidation of Trp-P-2-(NHOH), the mutagenicity slowly and continuously decreased, until it was finally lost almost completely. Similar acceleration by SOD of aerobic oxidation was found for 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [Glu-P-1(NHOH)]. Again, mutagenicity of approximately 1/4 that of the original was retained in the SOD-mediated decomposition, while a complete loss of the mutagenicity was observed in the spontaneous decomposition. When Trp-P-2(NO) was treated with the superoxide-generating system, xanthine oxidase plus xanthine, Trp-P-2(NHOH) was formed. Therefore, the role of SOD in the conversion of Trp-P-2(NHOH) into Trp-P-2(NO) is the removal of superoxide anions generated by reduction of aerobic oxygen, thereby inhibiting the reverse reactions, i.e. the reduction of Trp-P-2(NO) and that of the putative intermediate nitroxide radical. In support of this proposed mechanism, phenylhydroxylamine underwent a SOD-accelerated conversion to nitrosobenzene, and nitrosobenzene was reduced to phenylhydroxylamine by the action of the xanthine oxidase-xanthine system. Hence, this reversible interchange between an arylhydroxylamine and its nitroso compound, coupled with the oxygen-superoxide cycle, may be a general phenomenon. A consequence of this finding is that the xenobiotic N-hydroxylamines may be converted by the action of SOD in the biological settings into nitroso compounds, which are chemically more stable, serving as a reservoir for mutagenicity.
Carcinogenesis 1988 Nov
PMID:Superoxide dismutase-mediated reversible conversion of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole, the N-hydroxy derivative of Trp-P-2, into its nitroso derivative. 284 95

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

To help clarify whether elevation of gamma-glutamyltranspeptidase (GGT) in hepatocytes is associated with particular pattern(s) of liver differentiation, adult rat hepatocytes in primary culture were maintained for up to 5 days under conditions considered to alter differentiation in liver or other cells: basal GGT activity in untreated cultures and inducibility of the enzyme by known inducers such as dexamethasone, p,p'-dichlorodiphenyltrichloroethane or pregnenolone 16 alpha-carbonitrile were measured. Basal and induced GGT activities were maximal in confluent cultures and declined with decreasing cell density, an effect probably mediated by cell contact rather than factors in the culture medium. Opposite effects of cell density on GGT and DNA synthesis suggest that increased GGT activity is not linked with growth. Epidermal growth factor (EGF) increased basal GGT and augmented the action of xenobiotic inducers in lower density cultures, giving GGT activities approaching the levels in confluent cells. EGF had no effect on confluent cultures. Activators of protein kinase C such as tetradecanoyl phorbol acetate had significant but small inducing effects on GGT. Agents including all-trans retinoic acid, butyrate and dimethylsulfoxide which are considered to favour terminal differentiation in many cell types, all partly blocked induction of GGT by dexamethasone, EGF or xenobiotics. The results are consistent with (but do not prove) the view that elevated GGT activity may be associated with liver phenotype(s) distinct from terminal differentiation but not necessarily linked with growth.
Carcinogenesis 1987 Dec
PMID:Modulation of gamma-glutamyltranspeptidase in normal rat hepatocytes in culture by cell density, epidermal growth factor and agents which alter cell differentiation. 289 Apr 44

Formation of the N-(deoxyguanosin-8-yl)-aminofluorene adduct was studied in enzyme-altered foci induced by four different liver carcinogenesis models. Foci were detected and scored for enzyme phenotype by a computer-aided image overlay technique. Localization of the enzymes gamma-glutamyl transpeptidase, canalicular ATPase and glucose-6-phosphatase was performed by enzyme histochemistry, allowing identification of foci of seven different phenotypes. Patterns of foci obtained by image overlay were compared to in situ 2-acetylaminofluorene--DNA adduct distribution obtained by immunofluorescence. Foci were induced by the following models: (1) chronic feeding of 0.02% 2-acetylaminofluorene (2-AAF) for 8 weeks; (2) intubation of diethylnitrosamine (DEN) (10 mg/kg) 24 h after a 70% partial hepatectomy (PH), followed 8 weeks later by a diet containing 0.05% phenobarbital for 9 months; (3) intubation of DEN (10 mg/kg) 24 h after PH, followed by a diet containing 0.01% ciprofibrate for 5 months, and after an additional 4 months a diet containing 0.05% phenobarbital for 2 months; (4) maintenance for 7.5, 16.5 or 19.5 months after transplantation of DEN/2-AAF/PH ('Solt-Farber' protocol) donor liver cells into host rats receiving a brief 2-AAF/PH selective regimen then no further treatment until sacrifice. To test the capacity of both foci and morphologically normal livers to form DNA adducts, the animals in models 2-4 received a diet containing 0.02% 2-AAF for 5 or 6 days before sacrifice. In all of the enzyme-altered foci identified in models 1-3 there were no DNA adducts visible by immunofluorescence. Scattered groups of positive cells were occasionally seen in the otherwise dark foci induced by model 4. For technical reasons some enzyme-altered foci were not identifiable on the fluorescence-stained slides. In liver serial sections from rats in models 1-4, there were 75, 304, 125 and 68 enzyme-altered foci of seven different phenotypes which were identified as AF-DNA negative. In models 1 and 4 there were some additional adduct-negative foci not associated with any of the seven identified focus phenotypes. These studies demonstrate that loss of the ability to form DNA adducts in hepatic enzyme-altered foci is a common and very early biochemical adaptation to xenobiotic exposure in different hepatocarcinogenesis models. This adaptation also is retained by the majority of foci in later stages of hepatocarcinogenesis.
Carcinogenesis 1988 Apr
PMID:Lack of acetylaminofluorene--DNA adduct formation in enzyme-altered foci of rat liver. 289 93

This study was designed to explore further the hypothesis that the special resistance phenotype seen in hepatocyte nodules during liver carcinogenesis could have a physiologic correlate in the manner with which a carcinogenic xenobiotic is handled. Hepatocyte nodules were induced in male rats by continuous or intermittent exposure to dietary 2-acetylaminofluorene over a 25-week period. Two or 5 weeks after the exposure, the animals were given a single dose of 9-14C-2-acetylaminofluorene. The amounts and rates of excretion of unconjugated compound and derivatives and of the glucuronic acid metabolites in the bile and urine and the amounts in the blood and liver were measured over a period of 180 minutes. For comparison, animals fed the basal diet alone, animals injected with phenobarbital or 3-methylcholanthrene, animals receiving a single dose of cobalt heme and animals fed the 2-acetylaminofluorene for only 2 weeks were studied. These groups were used as controls for different patterns of drug metabolism, especially relating to the cytochromes P-450. The nodule-bearing animals showed a pattern of handling of the carcinogen that is quite different than that of the animals of any other group. They excreted in the bile plus urine from 20 to 30% less. However, relatively much more was in the urine. The free and glucuronide-conjugated metabolic products of the carcinogen were assessed by high performance liquid chromatography. The nodule-bearing animals and the animals treated with 3-methylcholanthrene excreted much more glucuronic acid esters. The pattern of distribution of labeled 2-acetylaminofluorene is different in the nodule-bearing rats than in other animals in which variations in phase I and phase II drug-metabolizing enzymes were induced by treatment with cobalt heme, phenobarbital, 3-methylcholanthrene or short-term exposure to dietary 2-acetylaminofluorene.
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PMID:Kinetics of excretion of 2-acetylaminofluorene in normal and xenobiotic-treated rats and in rats with hepatocyte nodules. 292 79


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