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)

Metabolism of benzidine was assessed with rabbit renal inner medullary slices. 3-(Glutathion-S-yl)-benzidine was identified as a product of metabolism. This thioether conjugate was shown to be identical to synthetic conjugate by chromatographically assisted hydrodynamic voltammetric and enzymatic techniques. A good correlation between PGE2 synthesis and conjugate formation was observed with a variety of incubation conditions including tissue weight, arachidonic acid concentration and incubation time. With 0-0.01 mM idomethacin, an inhibitor of the fatty acid cyclo-oxygenase component of prostaglandin H synthase (PHS), a linear relationship between conjugate formation and prostaglandin E2 synthesis was observed. In contrast, the peroxidase cosubstrates propylthiouracil, phenidone, ascorbate and methimazole inhibited arachidonic acid stimulation of conjugate formation but not prostaglandin E2 synthesis. These cosubstrates may be functioning as competitive inhibitors of benzidine co-oxidation. The results are consistent with peroxidatic metabolism of benzidine in intact tissue by a PHS-mediated process. 3-(Glutathion-S-yl)-benzidine may be a useful marker for studying peroxidatic metabolism in intact tissue and in investigating selective inhibition of this process.
Carcinogenesis 1986 Jan
PMID:Peroxidatic metabolism of benzidine by intact tissue: a prostaglandin H synthase-mediated process. 308 Feb 49

Structural analogs of diethylstilbestrol (DES) with at least one phenolic hydroxyl group are metabolized by prostaglandin H synthase (PHS) from ram seminal vesicle microsomes (RSVM) in vitro in the presence of arachidonic acid (20:4). U.v. spectroscopy revealed the formation of p-quinoid intermediates in incubations of DES, tetrafluoro-DES and dimethylstilbestrol, and tautomerization of the quinones to the respective dien-compounds which were characterized by h.p.l.c. and GC/MS. Indomethacin inhibits the formation of these metabolites which are identical to the major metabolites formed in incubations with horseradish peroxidase/hydrogen peroxide. Covalent binding to protein was observed in incubations of PHS co-substrates. Notably, formation of reactive intermediates which bind to protein is not limited to DES-analogs which form quinone intermediates: radiolabeled hexestrol and E,E-dienestrol yield protein-bound radioactive products upon incubation with RSVM and 20:4, probably via one electron-oxidation to a phenoxy radical. PHS-catalyzed metabolism of structural analogs of DES is accompanied by a concentration-dependent increase in cyclo-oxygenase activity. The measurement of the 20:4-dependent oxygen uptake rates in vitro can serve as a convenient assay for estrogenic compounds which undergo co-oxidation. At high concentrations, however, DES structural analogs can inhibit rather than stimulate PHS. The PHS-catalyzed formation of reactive intermediates from DES structural analogs and their effect on PHS may be of importance for their biological activity in estrogen target tissues with low mono-oxygenase activity.
Carcinogenesis 1986 Jan
PMID:Co-oxidation of diethylstilbestrol and structural analogs by prostaglandin synthase. 308 Feb 50

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]-hydrazide (FNT) is a renal carcinogen in the rat. The peroxidative activity of prostaglandin H synthase oxidizes FNT into a reactive intermediate which forms 5-(S)-substituted thioether conjugates with glutathione and N-acetylcysteine. These conjugates are also formed during horseradish peroxidase oxidation of FNT. The conjugate was identified by the combined results of comparative u.v./vis. spectrophotometry, chromatographically-assisted hydrodynamic voltammetry and proton n.m.r. spectroscopy. The relative rate of PHS metabolism of FNT was similar to that observed with benzidine and 5-fold faster than ANFT, its 5-nitrofuro-2-aminothiazole analogue. These results indicate that the pathogenic effects of FNT may be caused by its peroxidative activation and that cellular thiols may attenuate the toxic effects of FNT by conjugate formation.
Carcinogenesis 1986 Sep
PMID:Metabolism of the renal carcinogen FNT by peroxidases. 309 Dec 81

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.
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PMID:Effects of combined treatments with selenium, glutathione, and vitamin E on glutathione peroxidase activity, ornithine decarboxylase induction, and complete and multistage carcinogenesis in mouse skin. 309 11

The ability of eight different aromatic amines to serve as reducing substrates for the conversion of 5-phenyl-4-pentenyl-hydroperoxide to 5-phenyl-4-pentenylalcohol by prostaglandin H synthase (PHS) was studied. The methodology used a direct assay for the reduction of hydroperoxide to alcohol and allowed an assessment of the reducing substrates' efficiency as a donor of electrons to the peroxidase component of highly purified PHS. The eight amines tested include, 1-naphthylamine, 2-naphthylamine, 2,4-diaminoanisole, 2,5-diaminoanisole, 2-aminofluorene, 2-acetylaminofluorene, 2-amino-anthracene and benzidine. The compounds tested were either very efficient substrates or showed minimal activity as reducing substrates. Benzidine, 2,4-diaminoanisole and 2,5-diaminoanisole were excellent substrates providing nearly stoichiometric hydroperoxide reduction even at low enzyme concentrations. On the other hand, the five remaining compounds showed no activity as reducing substrates. Increases in enzyme and/or substrate concentration still did not produce any significant enzymatic activity with the poor substrates. The results of these investigations provide important information concerning the metabolic activation of these aromatic amines by PHS. There is evidence in the literature that some of these amines are metabolized by PHS to mutagenic and carcinogenic species. For the efficient reducing substrates this remains a reasonable suggestion. However, for the poor reducing substrates, alternative possibilities for the oxidizing agent must be considered.
Carcinogenesis 1987 Mar
PMID:Reducing substrate activity of some aromatic amines for prostaglandin H synthase. 310 98

3-Amino-1,2,4-triazole, a thyroid carcinogen and goitrogen, is negative in a wide variety of short-term mutagenicity assays. However, amitrole induces gene mutations and morphological transformation in Syrian hamster embryo fibroblasts, cells known to carry out the prostaglandin H synthase (PHS)-mediated peroxidative metabolism of other carcinogens. Therefore, we have investigated the peroxidase-mediated binding of [14C]amitrole to macromolecules in vitro. We report here the PHS- and lactoperoxidase-catalyzed binding of [14C]amitrole to protein and tRNA, as well as protein binding by rat and hog thyroid peroxidase. PHS was an order of magnitude more active than lactoperoxidase and two orders of magnitude more active than thyroid peroxidase. The low levels of binding observed with thyroid peroxidase could be explained by the rapid and potent inhibition of this enzyme by amitrole. Although the thyroid peroxidase-mediated binding of amitrole was quite low, it was not inhibitable by compounds that would be expected to be competing substrates in vivo (i.e. I-, monoiodotyrosine, diiodotyrosine). Neither catalase nor horseradish peroxidase catalyzed binding of [14C]amitrole. It was also observed that an interaction between amitrole and protein and/or nucleic acid resulted in the slow generation of hydrogen peroxide, which then served as a substrate to drive peroxidase-mediated binding of [14C]amitrole. These data suggest that PHS may be responsible for conversion of amitrole to a mutagenic intermediate in Syrian hamster embryo cells. Furthermore, the generation of reactive metabolites of amitrole by thyroid peroxidase and/or PHS may contribute to the complete carcinogenicity of this compound by adding a mutagenic response to its potent hormonal effects.
Carcinogenesis 1987 May
PMID:Macromolecular binding of the thyroid carcinogen 3-amino-1,2,4-triazole (amitrole) catalyzed by prostaglandin H synthase, lactoperoxidase and thyroid peroxidase. 310 50

Methapyrilene ([14C]MPH) was found to bind to calf thymus DNA only after activation by both rat liver microsomes and NADPH. The cytochrome P-450 inhibitors 2,4-dichloro-6-phenylphenoxyethylamine, 2-diethylaminoethyl-2,2-diphenylvalerate and metyrapone inhibited binding, but methimazole, a flavin-dependent monooxygenase inhibitor, had no effect. However, 1,2-epoxy-3,3,3-trichloropropane, an epoxide hydrolase inhibitor, decreased binding by 30%. Pre-treatment of rats with isosafrole, pregnenolone-16 alpha-carbonitrile or phenobarbital had little or no effect on binding while 3-methylcholanthrene pretreatment decreased binding by 37%. Incubations in the presence of either N-acetylcysteine, glutathione, catalase or glutathione-peroxidase decreased binding to DNA while superoxide dismutase had no effect. These data suggest that MPH is metabolically activated to a species which binds to DNA and that this activation may be mediated by cytochrome P-450 isozymes.
Carcinogenesis 1987 Oct
PMID:Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro. 311 19

Male ACI/N rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water, and in conjunction with histological examination, the changes of the expressed cytochrome P-450 components in the urothelium and other tissues (liver, kidney, esophagus, intestines) were examined by means of immunohistochemistry. Frozen tissue sections were prepared and immunostained with anti-rat cytochrome P-450 monoclonal antibodies and an avidin-biotin-peroxidase complex. Monoclonal antibodies used were APH-3 and APH-8 raised against a high-spin form of cytochrome P-448, APL-1 and APL-2 against a low-spin form of cytochrome P-448, and APF-3 against cytochrome P-450. BBN-induced qualitative and quantitative changes of cytochrome P-450 components recognized by these monoclonal antibodies were not observed in tissues other than the bladder. Untreated rat bladder epithelium was not stained with any of these 5 monoclonal antibodies. The treatment with BBN for more than 3 weeks, however, resulted in the expression of cytochrome P-450 component(s) recognized by APH-8 antibody. This cytochrome P-450 component increased with the advance of carcinogenic changes in the urothelium. The component reactive with AHP-8 was also detected in the cancer tissues of transplantation lines of rat bladder cancers. In contrast, the cytochrome P-450 components recognized by APL-1, APL-2 or APF-3 were undetectable or present at low levels throughout the BBN carcinogenesis. These results suggest that a certain cytochrome P-450 component(s), probably a high-spin form of cytochrome P-448, is selectively induced in urothelium in association with neoplastic bladder lesion.
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PMID:Altered expression of immunohistochemically detected cytochrome P-450 component(s) in nitrosamine-induced rat urinary bladder lesion. 311 31

Although the peroxidative metabolism of benzidine and other carcinogenic arylamines has been regarded as a significant pathway in extrahepatic tissues, the mechanism of peroxidase-mediated covalent binding to DNA has remained unclear. In this study, we have compared the metabolic activation of benzidine by prostaglandin H synthase, horseradish peroxidase, chloroperoxidase, and lactoperoxidase. All four peroxidases mediated the binding of benzidine to DNA and equimolar amounts of hydrogen peroxide (or arachidonic acid) and benzidine were required for the maximal binding in the system with either horseradish peroxidase or prostaglandin H synthase. In reactions containing both synthetic [3H]benzidine diimine and [14C]benzidine, rapid equilibration of both compounds was evident through the formation of its charge-transfer complex and the 14C-associated binding to DNA. However, the total binding (3H and 14C) correlated with the concentration of benzidine diimine rather than that of the charge-transfer complex. Two major and one minor deoxyguanosine adducts (P-I, P-III and P-IV, respectively) were isolated after the enzymatic hydrolysis of the benzidine-modified DNA. P-I was identified as N-(deoxyguanosin-8-yl)-benzidine, which was the major adduct formed by reaction of benzidine diimine with DNA. P-IV, which was also formed on reaction of benzidine diimine with DNA, was consistent with an N-(deoxyguanosin-N2-yl)-benzidine structure. P-III, which was formed only in the peroxidase incubations with DNA, was characterized as a novel N,3-(deoxyguanosin-N7,C8-yl)-benzidine derivative. Furthermore, this DNA adduct was shown to arise by the action of the peroxidase on DNA that had been previously modified by benzidine diimine. These results indicate that the two-electron oxidation product of benzidine, benzidine diimine, is the predominant reactive intermediate for the DNA binding mediated by peroxidases.
Carcinogenesis 1988 Sep
PMID:Mechanism of formation and structural characterization of DNA adducts derived from peroxidative activation of benzidine. 313 47

The peroxidase-catalyzed metabolism of (bi)sulfite (hydrated sulfur dioxide) in the presence of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) was examined. Both horseradish peroxidase and prostaglandin peroxidase catalyze the one-electron oxidation of (bi)sulfite. This results in the formation of a sulfur trioxide radical anion which then reacts with molecular oxygen to form a peroxyl radical. This (bi)sulfite-derived peroxyl radical then reacts with BP-7,8-diol to form BP-7,8-diol-9,10-epoxides, the ultimate carcinogenic form of benzo[a]pyrene (BP). Addition of (bi)sulfite to incubations containing BP-7,8-diol and an active peroxidase resulted in significantly increased levels of BP diol-epoxide formation. This result may, in part, explain the reported co-carcinogenic effect of sulfur dioxide on BP-induced tumors in the respiratory tracts of rats and hamsters. The sulfur trioxide radical anion also reacts directly with BP-7,8-diol to form a sulfonate adduct. This reaction was particularly significant under conditions where molecular oxygen was depleted from the incubations. While the significance of this particular adduct is not known, its formation suggests that the sulfur trioxide radical anion generated during the peroxidase-catalyzed oxidation of (bi)sulfite could react with a wide assortment of compounds to form sulfonate adducts.
Carcinogenesis 1988 Nov
PMID:Peroxidase-catalyzed oxidation of (bi)sulfite: reaction of free radical metabolites of (bi)sulfite with (+/-)-7,8-dihydroxy-7, 8-dihydroxy[a]pyrene. 314 Oct 75


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