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)

White suckers (Catostomus commersoni) are one of two species of bottom-feeding fish in which various liver neoplasms are more prevalent in urban/industrial sites in western Lake Ontario than in less polluted sites in the Great Lakes. Previous studies indicate that white suckers excrete metabolites of various polycyclic aromatic hydrocarbons (PAHs) in bile, and that glutathione transferase (GST)-mediated conjugation is a major detoxification pathway for the PAH benzo[alpha]pyrene. To determine whether hepatocarcinogenesis in these wild fish is associated with induced GST-dependent resistance to carcinogens, we examined the expression of immunoreactive GSTs in liver neoplasms and putatively preneoplastic altered hepatocellular foci from white suckers collected from several polluted sites in western Lake Ontario. Histological sections of liver with altered hepatocellular foci, hepatocellular adenomas, hepatocellular carcinomas, bile duct adenomas and bile duct carcinomas were examined for GST immunoreactivity by the peroxidase-antiperoxidase (PAP) technique with polyclonal antiserum specific for all major GST isoenzyme subunits found in normal liver of white suckers. All bile duct adenomas, bile duct carcinomas and hepatocellular carcinomas were markedly or completely deficient in immunoreactive GST in comparison with surrounding normal hepatocytes. The majority of the hepatocellular adenomas were also deficient. Most altered hepatocellular foci had normal GST staining, but several GST-deficient altered hepatocellular foci were observed. However, none of the preneoplastic or advanced liver neoplasms expressed induced GST, suggesting that carcinogenesis is not associated with selection for GST-dependent resistance. Loss of hepatocellular GSTs may be incidental to neoplastic progression in these fish, or might be important in increasing susceptibility of some preneoplastic populations of hepatocytes to further DNA damage by environmental or endogenous chemicals that are normally detoxified by GSTs.
Carcinogenesis 1991 Dec
PMID:Loss of glutathione S-transferases in pollution-associated liver neoplasms in white suckers (Catostomus commersoni) from Lake Ontario. 166 Jul 92

The present studies were undertaken to elucidate the mechanism(s) of the anti-neoplastic effect of diallyl sulfide (allyl sulfide, DAS), a naturally occurring organosulfide abundant in vegetables of the Allium genus, against benzo[a]pyrene (B[a]P)-induced carcinogenesis in the mouse. DAS treatment caused a significant increase in glutathione S-transferase (GST) activity, an enzyme system responsible for detoxification of a variety of electrophilic xenobiotics including several harmful B[a]P metabolites, of mouse stomach in a dose-dependent manner. This activity in the stomach of mice treated with 25, 50 and 75 mumol DAS was higher by 1.13-, 1.20- and 1.58-fold, respectively, when compared to the control. Purification and quantitation of GST from equal amounts (1.2 g) of control and 50 mumol DAS-treated mice stomach tissues demonstrated that elevation in activity occurred as a result of increased de novo synthesis of the enzyme protein. DAS treatment also resulted in increased pulmonary GST activity, but not in a dose-dependent fashion. On the other hand, treatment of mice with DAS did not alter hepatic GST activity. Interestingly, a small but statistically significant (P less than or equal to 0.05) reduction in kidney GST activity was observed in mice treated with 50 or 75 mumol DAS, as compared to the control. The effect of DAS treatment was also assessed on glutathione (GSH) peroxidase activity, another GSH-dependent detoxification enzyme, in mouse tissues. Treatment of animals with 25, 50 and 75 mumol DAS increased stomach GSH peroxidase activity by 1.64-, 1.93- and 2.52-fold, respectively, over the control. This enzyme activity in the lungs of mice treated with 25, 50 and 75 mumol DAS was higher by 1.44-, 1.54- and 1.21-fold, respectively, when compared to the control. On the other hand, GSH peroxidase activity in liver and kidney was unchanged by DAS treatment. These results suggest that DAS and perhaps other naturally occurring organosulfur compounds may exert an anti-neoplastic effect by modulating GSH-dependent detoxification enzymes.
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PMID:Effect of diallyl sulfide, a naturally occurring anti-carcinogen, on glutathione-dependent detoxification enzymes of female CD-1 mouse tissues. 188 35

o-Phenylphenol (OPP) and its sodium salt sodium ortho-phenylphenate (NaOPP) are broad spectrum fungicides and antibacterial agents. Both are urinary bladder and renal carcinogens in the Fischer 344 rat. OPP is converted by mixed-function oxidases in the liver to phenylhydroquinone (PHQ). Since appreciable amounts of prostaglandin (H) synthase (PGS) are found in rat bladder and kidney-medullary papilla, the target sites of OPP- and NaOPP-induced tumors, we hypothesized that a secondary PGS-mediated activation of PHQ to phenylbenzoquinone (PBQ) may occur in the bladder and kidney. We have studied the metabolism of PHQ by PGS in the presence of arachidonic acid and hydrogen peroxide as co-factors. These studies showed that PHQ is indeed metabolized to a product having identical spectral and electrochemical properties to PBQ. The disappearance of PHQ with time was stoichiometric to the formation of PBQ. Less than 10% of PHQ was converted to PBQ in the absence of enzyme, indicating that auto-oxidation may play only a minor role in the conversion of PHQ to PBQ. Similar results were obtained when PGS was replaced with either myeloperoxidase or horseradish peroxidase and hydrogen peroxide as co-factor. These studies suggest that the peroxidative metabolism of PHQ by PGS to the reactive PBQ could play an important role in OPP-induced urinary bladder and kidney carcinogenesis in rats.
Carcinogenesis 1991 Jan
PMID:Metabolism of phenylhydroquinone by prostaglandin (H) synthase: possible implications in o-phenylphenol carcinogenesis. 189 53

The formation and stability of benzo[a]pyrene DNA adducts were studied in tissues of BALB/c mice exposed to benzo[a]pyrene (B[a]P). The DNA adducts were visualized with an immunocytochemical peroxidase staining technique using an antiserum specific for the major B[a]P-derived adduct in DNA [(+/-)trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE-N2-dG)]. The nuclear staining density was measured by microdensitometry. When mice were treated with an increasing dose of B[a]P the nuclear staining increased in the tissues studied (lung, heart and kidney). A linear relationship was found between the immunocytochemical nuclear staining signal and the actual DNA adduct level in the lung as measured by 32P-postlabeling. Maximum adduct formation was found 5 days after a single i.p. injection of B[a]P. Adduct levels decreased gradually after 7 days, but even after 61 days a slight specific staining was still present, suggesting that not all adducts had disappeared at that time. As judged from the disappearance of [3H]thymidine from prelabeled DNA the loss of adducts from the lung was not a result of DNA repair but one of cell turnover. In human white blood cells B[a]P-derived adducts could be detected after in vitro incubation with the reactive metabolite of B[a]P (BPDE). Dose-response studies demonstrated a positive relationship between BPDE-DNA adduct formation, the immunocytochemical staining signal and the BPDE concentration in the culture medium.
Carcinogenesis 1991 Mar
PMID:Immunocytochemical visualization of DNA adducts in mouse tissues and human white blood cells following treatment with benzo[a]pyrene or its diol epoxide. A quantitative approach. 190 Dec 49

Expression of blood group-related antigens and the binding pattern of Ulex europaeus-I (UEA-I) in fetal and newborn hamster pancreases was examined immunohistochemically by monoclonal antibodies (MoAbs) against blood group antigens and by peroxidase-conjugated UEA-I. The fetal hamster pancreas was detected histologically at the 12th day of gestation. MoAbs A, B and Le(a) were not immunoreactive with pancreatic cells in any stage of development nor were they after birth. Le(x) was first expressed in the luminal surface of duct cells at the 13th day of gestation, disappeared at the 15th day of gestation, was re-expressed after birth in acinar cells and was absent in the adult pancreas. Le(b) and Le(y) were expressed in acinar cells in late fetal and early newborn stages, but disappeared with maturation and were absent in the adult pancreas. UEA-I binding, however, was demonstrated in both fetal and adult pancreatic tissue. In cancer cells induced by BOP, blood group antigens except for Le(a) and UEA-I binding were found in various reactivity. These findings suggest that in hamsters (i) A and B antigens are tumor-related antigens; (ii) H, Le(b), Le(x) and Le(y) are oncofetal antigens; and (iii) fucosylation is an important event in cell differentiation.
Carcinogenesis 1990 Apr
PMID:Blood group antigen expression in developing pancreas and in induced pancreatic cancer cells in Syrian hamsters. 196 74

Sodium nitrite was shown to enhance the metabolism of trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) to 7/8,9,10- and 7,10/8,9-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (tetraols) in phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocytes (PMNs). The production of these tetraols implicates the intermediate formation of the corresponding trans-7,8-dihydroxy-9,10-epoxy-7,8-9,10-tetrahydrobenzo[a]pyrene (anti-BPDE). A 2- to 3-fold increase in the tetraol yield was observed in the presence of nitrite in excess of 1 mM. Sodium azide, an inhibitor of myeloperoxidase and catalase, reduced the nitrite-stimulated metabolism of BP-7,8-diol in PMA-activated leukocytes. Diphenylene iodonium sulphate, a NADPH-oxidase inhibitor, lowered the production of tetraols in PMA-stimulated leukocytes both in the absence and presence of nitrite. Additionally, nitrite markedly enhanced the covalent binding of metabolites derived from [3H](-)-BP-7,8-diol to leukocyte proteins as well as to DNA present extracellularly. The nitrite-stimulated covalent binding to both proteins and DNA was inhibited by the presence of sodium azide. The mechanism underlying the effect of nitrite on the metabolism of BP-7,8-diol to reactive intermediates in PMA-activated human polymorphonuclear leukocytes is not known. However, the results are compatible with a peroxidase-dependent mechanism although other possible pathways may contribute to the enhanced rate of metabolism.
Carcinogenesis 1991 May
PMID:Sodium nitrite-stimulated metabolic activation of benzo[a]pyrene 7,8-dihydrodiol in human polymorphonuclear leukocytes. 202 41

We have attempted in this article to summarize and review cooxidation reactions that occur during the metabolism of AA and potential roles that these reactions can play in the activation and detoxification of chemicals. This review summarizes approximately 15 years of intensive investigation by a number of laboratories, and as such not all studies are cited, and in some cases data are not discussed with the emphasis that the original investigators may have intended. The major focus of many of these studies has been toward carcinogenesis. In the future, emphasis may shift to the formation of metabolites that will lead to other toxic effects. The cooxidation reactions that occur during AA metabolism are dependent upon the peroxidase activity of PHS. For some chemicals that are not cosubstrates, the epoxidation reactions that occur are dependent upon the subsequent formation of peroxyl radicals. A large and diverse number of chemicals are metabolized by an equally large and diverse number of chemical reactions. The unifying theme is the free radical nature of these oxidations. The subsequent reactions that these chemicals undergo is dictated by the nature of the free radical and the environment in which it is generated. Ample evidence now exists for the contribution of these free radical-mediated reactions not only in the formation of toxic metabolites, but also in some cases in the detoxification of chemicals. The overriding factor for this type of metabolism to occur is the relative concentrations in the specific tissue of PHS and peroxyl radicals with respect to other activating systems, particularly the monooxygenase system. In vivo investigations support the importance of the peroxidase and peroxyl radical systems in both activation and detoxification of chemicals in extrahepatic tissues.
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PMID:Prostaglandin H synthase and xenobiotic oxidation. 211 54

The mechanism of activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) was investigated by comparison with benzidine. In comparison with benzidine, ANFT has a higher electrochemical potential (approximately 700 mV) and is less effective as a reducing co-substrate for either prostaglandin H synthase (PHS) or horseradish peroxidase. Activation was monitored by measuring binding to protein (BSA) and DNA. ANFT binding to protein was reduced by indomethacin, a fatty acid cyclooxygenase inhibitor; phenol and aminopyrine, competitive reducing co-substrates; ascorbic acid, an antioxidant; and glutathione, thioether conjugate formation. These results are consistent with those previously reported for benzidine and demonstrate a peroxide co-substrate requirement, interaction of peroxidase with amine, formation of reactive intermediates and inactivation of reactive intermediates. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO), a radical trap, also reduced ANFT binding to protein. Similar results were observed whether activation by PHS or horseradish peroxidase was investigated. Peroxidative activation of ANFT and benzidine to bind DNA was inhibited by these test agents in a manner similar to that observed with protein except that DMPO did not reduce binding. In addition, 2-methyl-2-nitrosopropane and methyl viologen, which are radical traps, and methionine and p-nitrobenzyl-pyridine, which are strong nucleophiles, did not reduce ANFT or benzidine binding to DNA. These agents also did not prevent binding of benzidinediimine, the two-electron product of benzidine oxidation, to polydeoxyguanosine. Glutathione inhibited diimine binding by forming a conjugate. Results demonstrate that activation of ANFT to bind protein and DNA is similar to benzidine. Peroxidative activation of benzidine occurs by both one- and two-electron oxidation. A similar mechanism would explain ANFT binding to protein (one electron) and DNA (two electron).
Carcinogenesis 1990 Nov
PMID:Mechanism of peroxidative activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT): comparison with benzidine. 212 82

The p 21 product of ras oncogene has been detected immunohistochemically in normal, inflammatory, benign and malignant human thyroid tissues. With the monoclonal antibody SCI-oncogene I and an avidin-biotin-peroxidase complex (ABC), the expression of ras p 21 was evaluated in paraffin-embedded sections. The results showed that papillary and follicular adenocarcinomas of the thyroid had moderate to intense staining for ras p 21 in most cases. Cytoplasmic and apical surface staining were the most common patterns of immunoreactivity. Adenomas showed slight positive or negative staining in cytoplasm. Normal thyroid tissues and thyroiditis were uniformly negative. Grave's disease revealed slight to moderate staining in some cases. These findings suggest that ras oncogene is involved in carcinogenesis of thyroid carcinomas. Enhanced expression of ras p 21 may be useful in differentiation of thyroid adenocarcinomas from adenomas and may be a valuable parameter in evaluating biological behavior of tumors.
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PMID:[Expression of ras oncogene product P21 in thyroid tumors: an immunohistochemical study]. 216 39

Human blood cells, separated by Ficoll-Hypaque centrifugation, were tested for their ability to catalyze the formation of DNA adducts of 2-aminofluorene (AF), using the 32P-postlabeling procedure for adduct analysis. Incubation of neutrophils with AF, hydrogen peroxide and exogenous DNA yielded a single DNA adduct identified as C8-(N2-aminofluorenyl)-deoxyguanosine-3'-5'-diphosphate (AFdG) by cochromatography with a standard sample. AFdG levels in intact cells, lysed cells and in the granule fraction prepared from cell lysates were 102, 894 and 240 AFdG adducts/10(9) nucleotides/30 min respectively. AFdG levels corresponded to the activity of neutrophil peroxidase in these preparations. The monocyte/lymphocyte fraction yielded a low amount of 30 and 40 AFdG/10(9) nucleotides/30 min in the presence of hydrogen peroxide and of NADPH respectively. Erythrocytes did not generate a detectable level of AFdG, neither as intact cells nor as cell lysates. Whole blood samples likewise did not generate AFdG. Our findings reveal that, among blood cells, only neutrophils are capable of forming a biologically significant DNA adduct of aminofluorene in reasonable amounts and suggest that myeloperoxidase was the catalyzing enzyme.
Carcinogenesis 1990 Aug
PMID:Capability of human blood cells to form the DNA adduct, C8-(N2-aminofluorenyl)-deoxyguanosine-3'-5'-diphosphate from 2-aminofluorene. 216 84


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