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

Activation of polycyclic aromatic hydrocarbons (PAH) by horseradish peroxidase (HRP) with H2O2 has been studied as a model system for one-electron oxidation. This peroxidase has been used to catalyze binding of 6-[14C]methylbenzo[a]pyrene (BP-6-CH3) to DNA, which was purified, hydrolyzed to deoxyribonucleosides and analyzed by high pressure liquid chromatography (HPLC). The predominant hydrocarbon-DNA adduct observed was identified as BP-6-CH3 bound at the 6-methyl group to the 2-amino group of dG, confirming that activation by HRP occurs by one-electron oxidation. When DNA from mouse skin treated in vivo with [14C]BP-6-CH3 was purified, hydrolyzed and analyzed by HPLC, a profile was observed which was qualitatively similar to that from the peroxidase system. In particular, the identified adduct with the hydrocarbon bound at the 6-methyl group to the 2-amino group of dG was obtained. These results demonstrate that one-electron oxidation is the mechanism of activation by HRP for aromatic hydrocarbons and indicate that the same mechanism may occur in mouse skin, a target tissue for hydrocarbon carcinogenesis.
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PMID:Structure elucidation of a 6-methylbenzo[a]pyrene-DNA adduct formed by horseradish peroxidase in vitro and mouse skin in vivo. 664 Jul 83

The incidence of DMBA-induced mammary carcinomas in Sprague-Dawley rats depends upon their previous reproductive histories. Young virgin rats (YV) are highly susceptible to the carcinogen, while old virgin rats (OV) are less susceptible, and parous rats (P) are resistant. The authors performed endocrinologic studies in these three groups of rats in order to determine whether the different susceptibility to carcinogenesis, according to the reproductive history, is or is not related to the hormonal milieu. The pituitary, the ovaries, the adrenals, and the mammary glands were processed for light microscopy. Pituitary prolactin (PRL), follicle-stimulating hormone, and luteinizing hormone cells were immunostained by peroxidase-antiperoxidase and quantitated with an image analyzer. Radioimmunoassays of serum and pituitary PRL and serum estradiol were also done. The results showed no differences in the hormonal milieu of YV, OV, and P rats at the time of carcinogen treatment. Several changes were observed after DMBA administration, the most conspicuous being 1) hyperplasia of pituitary PRL cells, 2) high serum PRL levels, 3) nodular hyperplasia of the adrenal cortex, 4) high serum estradiol levels, and 5) lack of adrenal necrosis in P rats and some OV rats. These modifications did not correlate with the degree of susceptibility of YV, OV, and P rats to carcinogenesis, supporting the concept of the importance of the mammary gland differentiation at the moment of carcinogen administration. (Am J Pathol 1982, 109:47-56).
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PMID:Endocrinologic milieu and susceptibility of the rat mammary gland to carcinogenesis. 681 28

Certain carcinogens are thought to induce renal and bladder cancer following metabolic activation. We propose a model system for this activation and provide supporting experimental evidence. This model proposes that renal and bladder carcinogens' entry into the urinary tract is facilitated, that carcinogens are activated by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase (PES), and that activation results in covalent binding to nucleic acids which can initiate carcinogenesis. Benzidine and the 5-nitrofuran HMN were shown to inhibit uptake of organic anions and cations, respectively. Carcinogen binding to DNA was dependent upon specific unsaturated fatty acid substrates and prevented by specific inhibitors of PES, i.e., aspirin. Activation with organic peroxides or H(2)O(2) was inhibited by antioxidants but not aspirin. Horseradish peroxidase (HRP) metabolized benzidine but not ANFT. Acetaminophen and the 5-nitrofurans ANFT and HMN prevented PES (14)C-benzidine metabolism. However, only acetaminophen inhibited HRP metabolism of benzidine. The only aerobic metabolism we have observed of 5-nitrofurans is PES-catalyzed. Aspirin (0.5% in the diet) inhibited rat bladder hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin synthesis and PES metabolism of FANFT. After one year of an ongoing long-term study, gross examination reveals bladder tumors in 85% of the rats fed 0.2% FANFT and in only 37% of the rats fed FANFT plus 0.5% aspirin.
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PMID:Prostaglandin hydroperoxidase-catalyzed activation of certain N-substituted aryl renal and bladder carcinogens. 683 96

Bioactivation of carcinogens by peroxidases has received increasing attention since the discovery of the oxidation of carcinogens by prostaglandin hydroperoxidase. Benzidine and 3,5,3',5'-tetramethylbenzidine are oxidized by horseradish peroxidase and prostaglandin synthase to two-electron oxidation products (di-imines). Di-imines readily react with the phenolic anti-oxidant butylated hydroxyanisole to form adducts. In this paper, we have studied the oxidation of benzidine by horseradish peroxidase in the presence of phenolic compounds and characterized the resultant benzidine/phenol adducts. A benzidine/2,6-dimethylphenol adduct was isolated and characterized by mass spectrometry and high field n.m.r. The reaction of [14C]benzidine in the presence of horseradish peroxidase and phenol yielded only the benzidine/phenol adduct. Our results indicate that the benzidine/phenol adducts are analogous to the indoaniline dyes, differing only in substitution of a biphenyl group for a benzene ring. The reaction of benzidine di-imine with endogenous phenols may represent a new pathway for detoxication, removing potentially harmful metabolites of benzidine.
Carcinogenesis 1982
PMID:Chemical structure of the adducts formed by the oxidation of benzidine in the presence of phenols. 717 22

The expression and localization of glutathione S-transferase (GST) isoenzymes in the epithelium of normal oral mucosa (n = 9), overlying reactive fibrous hyperplasia (n = 9), and of potentially malignant [leukoplakia (n = 25), submucous fibrosis (n = 12), verrucous hyperplasia (n = 16)] and malignant [squamous cell carcinoma (n = 36), verrucous carcinoma (n = 13)] oral lesions were examined immunohistochemically using polyclonal antibodies raised against GST isoenzymes (alpha, mu and pi) with the standard avidin-biotin-peroxidase complex (ABC) method. GST alpha, mu and pi were almost completely absent in the epithelium of normal oral mucosa and overlying benign fibrous tissues. GST alpha staining was cytoplasmic and focally positive, while GST mu staining was similar to but weaker than that seen for GST alpha. GST pi showed both cytoplasmic and nuclear staining and was expressed in 60% of leukoplakias with mild dysplasia (n = 15), 80% of leukoplakias with moderate to severe dysplasia (n = 10). 75% of submucous fibrosis samples (n = 12), 75% of verrucous hyperplasias (n = 16), 77% of verrucous carcinomas (n = 13), 81% of well-differentiated squamous cell carcinomas (n = 26) and 70% of moderate- to poorly-differentiated squamous cell carcinomas (n = 10). In addition, GST pi expression was independent of the state of differentiation of oral cancers. Since GST pi was significantly over-expressed in the oral premalignant and malignant lesions, the kinetics of GST pi-positive cells and the value of GST pi as a tumor marker in oral carcinogenesis need further investigation.
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PMID:Immunohistochemical demonstration of epithelial glutathione S-transferase isoenzymes in normal, benign, premalignant and malignant human oral mucosa. 747 69

An increasing interest in fish species as sentinels of environmental pollution and in carcinogenesis research has led to the identification of diagnostically challenging neoplasms of uncertain cellular origin and the need for additional diagnostic methods. To determine the potential of using commercially available antibodies to intermediate filament proteins on paraffin-embedded fish tissues for immunocytochemistry in tumor diagnosis, the application of three antikeratin antibodies to normal adult tissues from two fish species was assessed. Multiple tissues from 12-14-in. striped bass (Morone saxatilis) and 6-month-old medaka (Oryzias latipes) of both sexes were fixed in Bouin's or formalin fixatives. Formalin-fixed neoplasms from several mammalian species, including cat, dog, hedgehog (Atelerix albiventris, Erinaceus europaeus), rhesus macaque (Macaca mulatta), and sloth bear (Melursus ursinus), were also used as positive controls. Using a strepavidin horseradish peroxidase method on paraffin-embedded tissues, the broad spectrum antibodies AE1/AE3 (Boehringer Mannheim, Indianapolis, IN) and MAK-6 (Triton Biosciences, Alameda, CA), which recognize most of the 19 human cytokeratins, and CAM 5.2 (Becton Dickinson, Mountain View, CA), which recognizes cytokeratins present in human liver, were used as primary antibodies. Epithelia from skin, gills, cornea, bile ducts, renal tubules, gastrointestinal tract, and thymus were strongly positive with AE1/AE3 and MAK-6 in striped bass, but nonepithelial tissues such as bone and muscle were negative. Skin, gills, cornea, and portions of the gastrointestinal tract were strongly positive in medaka with the same antibodies, whereas bile duct, renal, and intestinal epithelia were less so. Tissue digestion improved the intensity of staining, and fixation with Bouin's fixative improved results somewhat compared with formalin fixation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The immunocytochemistry of cytokeratin in fish tissues. 750 8

32P-Postlabeling analysis of the bisphosphate derivatives was conducted to characterize the DNA adducts generated from the peroxidase-mediated activation of N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP). Autoradiography of the D1 chromatogram of the postlabeled DNA hydrolysate revealed a major adduct (adduct 1) that migrated at Rf 0.15. An adduct with similar chromatographic characteristics was also obtained by postlabeling the products generated by chemical interaction of: (i) 2',6'-dichlorobenzoyloxy-4-acetylaminobiphenyl with the 3'-monophosphate of deoxyguanosine, and (ii) N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) with calf thymus DNA. The adduct derived from chemical reaction exhibited the same mobilities on two-dimensional TLC as that obtained from the peroxidase-mediated DNA binding of N-OH-AABP. Moreover, on HPLC analyses, these bisphosphate derivatives exhibited identical retention times, suggesting that structurally they might be the same. Furthermore, adduct 1 was insensitive to digestion with nuclease P1. In addition to adduct 1, another minor adduct (adduct 2) was also detected in the peroxidase-mediated DNA binding of N-OH-AABP. The adduct 2 in D1 exhibited an Rf of 0.66. Adduct 2 was also observed in the DNA sample chemically interacted with N-OAc-AABP. Both these adducts retained the acetyl moiety, which was confirmed by the presence of radioactivity in the hydrolysate of DNA derived by interaction with N-OAc-[14C-acetyl]AABP (labeled at the N-acetyl group). Based on proton NMR and MS analyses of the 5'-phospho analogs of adducts 1 and 2, the structures of these have been identified as 3-(deoxyguanosine-N2-yl)-4-acetylaminobiphenyl (dG-N2-AABP) and N-(deoxyguanosine-8-yl)-4-acetylaminobiphenyl (dG-C8-AABP). Analyses of the DNA samples obtained from human uroepithelial cells following exposure to N-OH-AABP revealed primarily the non-acetylated derivative N-(deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-ABP) with trace amounts of dG-N2-AABP. These results suggest that in the target cells for 4-aminobiphenyl carcinogenesis, the prevalence of the peroxidase mediated activation reaction of N-OH-AABP is relatively minor compared to the acetyltransferase pathway.
Carcinogenesis 1995 Sep
PMID:32P-postlabeling analysis of adducts generated by peroxidase-mediated binding of N-hydroxy-4-acetylaminobiphenyl to DNA. 755 68

Exposure to benzene, a human and animal carcinogen, results in the formation of structural chromosomal aberrations in the bone marrow and blood cells of animals and humans. The mechanisms underlying these clastogenic effects are unknown. Inhibition of enzymes involved in DNA replication and repair, such as topoisomerase enzymes, by the metabolites of benzene represents a potential mechanism for the formation of chromosomal aberrations. To test this hypothesis, the inhibitory effects of various phenolic and quinone metabolites of benzene on the activity of human topoisomerases I and II were studied in vitro. No inhibition of topoisomerase I was seen with any of the tested metabolites. Inhibitory effects on topoisomerase II were not observed for hydroquinone, phenol, 2,2'-biphenol, 4,4'-biphenol and catechol at concentrations as high as 500 microM. 1,4-Benzoquinone and 1,2,4-benzenetriol inhibited topoisomerase II at relatively high 500 and 250 microM concentrations, respectively. However following bioactivation using a peroxidase/H2O2 system, inhibitory effects were seen at concentrations as low as 50 microM for both phenol and 2,2'-biphenol and 10 microM for 4,4'-biphenol. The addition of reduced glutathione (GSH) to the 4,4'-biphenol and horseradish peroxidase reaction system protected topoisomerase II from inhibition suggesting that diphenoquinone or another oxidation product formed from 4,4'-biphenol might be the reactive species. These in vitro results indicate that inhibition of topoisomerase II may contribute to the clastogenic and carcinogenic effects of benzene. In addition, metabolites formed from these phenolic compounds appear to represent several new types of topoisomerase II-inhibiting compounds.
Carcinogenesis 1995 Oct
PMID:Topoisomerase inhibition by phenolic metabolites: a potential mechanism for benzene's clastogenic effects. 758 26

When [14C]tamoxifen was incubated with horseradish peroxidase and H2O2, two major metabolites, separated and identified by HPLC, were N-desmethyltamoxifen and tamoxifen N-oxide. Toremifene incubated in a similar system yielded N-desmethyltoremifene and toremifene N-oxide. No 4-hydroxylated metabolites were detected with either drug. When calf thymus DNA was included in peroxidase incubation mixtures, DNA damage, as assessed by 32P-postlabelling, could also be detected. The extent of damage caused by tamoxifen and toremifene was similar. The major adducts formed following incubation of DNA with tamoxifen had similar Rf values to two of the 32P-postlabelled adducts seen following dosing of rats with tamoxifen. Peroxidase was able to activate both drugs to derivatives which covalently bound to bovine serum albumin. The pH optimum for covalent binding and N-demethylation was near to pH 6.0. Results from liquid chromatography-electrospray secondary ion mass spectrometry suggest that tamoxifen and toremifene are metabolized by peroxidase to putative reactive epoxide intermediates responsible for the genotoxic effects. It is proposed that peroxidase oxidizes tamoxifen to a carbon-centred free radical which reacts with oxygen to form peroxy radicals capable of inserting an oxygen atom into tamoxifen. Lactoperoxidase and prostaglandin synthase are also able to catalyse tamoxifen N-demethylation and binding to protein. These data show that peroxidase can activate both tamoxifen and toremifene to an intermediate(s) that can damage DNA and covalently react with protein. Since it is known that women treated with tamoxifen can develop endometrial tumours, it may be relevant to determine whether activation of tamoxifen by peroxidases may contribute to its carcinogenic action at extrahepatic sites.
Carcinogenesis 1995 Mar
PMID:Peroxidase activation of tamoxifen and toremifene resulting in DNA damage and covalently bound protein adducts. 769 11

The potential importance of prostaglandin H synthase (PGHS) in the genotoxicity of fecapentaene-12 (fec-12) has been indicated by the finding that non-steroidal anti-inflammatory agents (NSAIDs) block the induction of oxidative DNA base damage by fec-12 in HeLa cells. To further investigate the role of PGHS in the metabolic 'activation' and genotoxicity of fec-12, we have measured: (i) oxygen uptake by fec-12 with purified preparations of PGHS; and (ii) the induction of DNA single-strand breaks (SSBs) in HeLa cells exposed to fec-12 in the absence or presence of PGHS inhibitors. Oxygen uptake occurred spontaneously with fec-12 alone but was stimulated 3-fold by the presence of PGHS. The potentiation of fec-12 oxygenation by PGHS was independent of arachidonate and inhibited 45% by indomethacin (INDO). Methylphenylsulphide (MPSI), a reducing substrate expected to compete with fec-12 in peroxidase-dependent co-oxidation reactions, also inhibited PGHS-mediated oxygen uptake with fec-12 by 55%. These results, together with the observation that the inhibitory effects of these agents in combination were additive, suggest that both the cyclooxygenase and peroxidase components of PGHS are involved in the oxidation of fec-12. INDO and MPSI also blocked the induction of DNA SSBs by fec-12 in HeLa cells, indicating that both components of PGHS are also involved in potentiating the genotoxicity of fec-12. It is proposed that this occurs in two ways: firstly, by formation of highly reactive fec-12 hydroperoxides which would generate oxygen radicals through Fenton-like reactions, and secondly, by the generation of oxygen radicals through peroxidase-mediated co-oxidation of fec-12.
Carcinogenesis 1995 May
PMID:Oxidation and genotoxicity of fecapentaene-12 are potentiated by prostaglandin H synthase. 776 60


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