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)

Several endogenous cellular constituents were tested for their ability to produce superoxide anion (O2-) from ground-state molecular oxygen upon irradiation by solar radiation. The pyridine cofactors NADPH and NADH, riboflavin, and the nucleosides 2-thiouracil and 4-thiouridine were found to sensitize the transmission of photon energy from solar radiation and monochromatic radiation (290, 334, 365, and 405 nm) to oxygen, resulting in O2- formation, as detected by superoxide dismutase-inhibitable cytochrome c reduction. Quantum yields for the production of O2- indicate that NADPH is the most efficient and riboflavin the least efficient of the compounds tested. These data indicate that endogenous compounds may participate in the production of O2- by solar radiation and imply that O2- may play a role in sunlight-induced erythema and dermal carcinogenesis.
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PMID:Superoxide anion is generated from cellular metabolites by solar radiation and its components. 301 63

Various mechanisms tend to reduce hexavalent chromium (Cr(VI] in the organism, both outside and inside target cells. A reducing activity has been demonstrated in the blood (mainly in erythrocytes), in secretions of the alimentary tract (saliva, gastric juice) and in the lumen of terminal airways (epithelial-lining fluid and alveolar macrophages). Preparations of several types of cells from various animal species--including human liver, lung parenchyma and bronchial tree cells--are capable of metabolically reducing Cr(VI) to a variable extent. This process can be ascribed to different cytoplasmic components, e.g. to mitochondria, microsomal fractions and especially to cytosolic fractions, where reduction is partly due to electron donors (e.g. glutathione) and mainly to NADPH-dependent enzyme activities, such as DT-diaphorase. Reduction is not only selectively stimulated by enzyme inducers but also, in rat lung cells, by the repeated intra-tracheal administration of Cr(VI) itself. All these reducing reactions are interpreted as detoxifying mechanisms, which constitute a threshold phenomenon in chromium carcinogenesis.
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PMID:Metabolic reduction of chromium as a threshold mechanism limiting its in vivo activity. 304 58

Racemic 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) is further metabolized by liver microsomes obtained from 3-methylcholanthrene pretreated rats in the presence of NADPH to at least four products as revealed by h.p.l.c. Data obtained from measurements by fluorescence spectroscopy under neutral and alkaline conditions and high resolution two-dimensional 1H n.m.r. spectroscopy on the major metabolite derived from anti-BPDE are consistent with aromatic hydroxylation at the 3-position either directly or indirectly via transient epoxide intermediates.
Carcinogenesis 1986 Jan
PMID:Studies by fluorescence and n.m.r. spectroscopy of the major product formed after further metabolism of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. 308 Feb 51

Metabolic activation and/or deactivation of indole alkaloid tumor promoter, (-)-indolactam V (ILV), was examined using rat liver microsomes. Reaction of ILV with the microsomes supplemented with NADPH and MgCl2 gave three major metabolites, which were identified as (-)-N13-desmethylindolactam V and two diastereomers of (-)-2-oxyindolactam V at C-3. The tumor-promoting activities of these metabolites were evaluated by induction of Epstein-Barr virus early antigen and inhibition of specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse epidermal particulate fraction, and proved to be conspicuously lower than that of ILV. These results demonstrate that the metabolism of ILV results in detoxification, and that it itself is the tumor-promoting entity. Studies on the enzymes concerned with this metabolism suggested the involvement of cytochrome P-450-containing mixed-function oxidases. Similar deactivation seems to be possible by skin, where the mixed-function oxidases are known to exist.
Carcinogenesis 1987 Jul
PMID:The metabolism of indole alkaloid tumor promoter, (-)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes. 310 58

The purpose of this work was to study the relative activities and stabilities of phase-I and phase-II drug metabolizing enzymes in incubation mixtures used in vitro genotoxicity testing in order to optimize the conditions of the assay, increase sensitivity and eliminate false negative results. Cytochrome P-450, NADPH-cytochrome P-450 (cytochrome c) reductase activity and various phase-I and phase-II enzyme activities of the drug-metabolizing system were determined in incubation mixtures used in liver microsomal assays. The behaviour of aminopyrine N-demethylase and p-nitroanisole O-demethylase activities as phase-I markers have been reported previously. Other activities measured were glutathione S-transferase, glutathione S-epoxide transferase and epoxide hydrase, and lipid peroxidation (LP) was determined. The experiments were carried out on liver S9 fractions derived from non-induced mice or mice induced with sodium phenobarbital (PB), and/or beta-naphthoflavone (beta-NF). The phase-II enzymes were much more stable (70-90% residual activity) than phase-I enzyme activities (35-60%) in all conditions tested. The residual cytochrome P-450 was approximately 70% stable and the remaining activity of NADPH-cytochrome c-reductase about 80%, indicating that this latter enzyme does not limit the rate of the monoxygenase system in these conditions. Phase-II enzymes were induced to a smaller extent (about 2 times) than in phase-I enzymes (5-6 times) by beta-NF + PB. NADPH-cytochrome c-reductase behaved as phase-II enzymes in this respect as well as for stability. LP was appreciably higher in non-induced than in induced animals. Treatment with the beta-NF + PB mixture, however, showed that induced enzymes were more stable than those obtained by simple induction with either beta-NF or PB alone. These results lead to the conclusion that prolonged incubation times in mutagenicity assays are unnecessary when considering the relative stabilities of the various phase-I and phase-II enzyme activities in the drug-metabolizing system.
Carcinogenesis 1987 Sep
PMID:Stability of drug metabolizing enzymes during the incubation conditions of the liver microsomal assay with non-induced and induced mouse liver S-9 fractions. 311 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

Studies were carried out, using antibodies to specific cytochrome P-450 isozymes, to identify the isozymes involved in the NADPH-dependent activation of 3,3'-dichlorobenzidine (DCB) by rat hepatic microsomes to mutagens in the Ames test. DCB activation was not affected by a monoclonal antibody specific for P-450c or by a monoclonal antibody specific for P-450b, but was inhibited 69% by a polyclonal antibody made against P-450d. DCB activation was also inhibited 46% by antibody specific for NADPH-cytochrome P-450 reductase. Further, addition of methimazole, a high affinity substrate for the flavin-containing monooxygenase, reduced the residual mutagenicity in the systems containing antibody to P-450d and cytochrome P-450 reductase to 9% and 19%, respectively, of the appropriate control values. It is concluded that P-450d contributes to a majority of the P-450-dependent activation of DCB in hepatic microsomes. The results also suggest that the flavin-containing monooxygenase may contribute to the microsomal activation of DCB.
Carcinogenesis 1988 May
PMID:Activation of 3,3'-dichlorobenzidine in rat liver microsomes to mutagens: involvement of cytochrome P-450d. 313 Feb 2

The levels of hydroperoxides in mouse skin (epidermis + dermis) homogenates incubated in the presence and absence of enzymic and non-enzymic generators of reactive oxygen species are rapidly increased by 12-O-tetradecanoylphorbol-13-acetate (TPA). Moreover, the homogenates prepared from skins treated repeatedly with TPA or 7,12-dimethylbenz[a]anthracene (DMBA) in vivo contain substantially more hydroperoxides, and accumulate more hydroperoxides in the presence of NaN3 and NADPH, than their counterparts prepared from control skins receiving acetone only. Various agents increase the levels of hydroperoxides in skin homogenates in relation with their tumor-promoting or carcinogen activities, suggesting that an increased level of peroxidation may be involved in the multistage process of skin carcinogenesis.
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PMID:Stimulation of hydroperoxide generation in mouse skins treated with tumor-promoting or carcinogenic agents in vivo and in vitro. 314 79

The 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a metabolite of the food mutagen--carcinogen IQ, was mutagenic to Salmonella TA98 (nitroreductase deficient). When either rat hepatic cytosol, NADPH (1 mM) or ascorbate (0.5 mM) was added to the mutagenicity assay, mutagenicity increased up to 15-, 10- and 50-fold respectively. In light of the effects of ascorbate and NADPH, it appears likely that hepatic cytosol may contain factors that protect N-hydroxy-IQ from oxidative decomposition. In contrast, hepatic monooxygenase metabolism of N-hydroxy-IQ decreased mutagenicity. When pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, was added to the mutagenicity assay, a dose-dependent inhibition of N-hydroxy-IQ mutagenicity was observed. 2,6-Dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O- acetyltransferase, did not inhibit the mutagenicity of N-hydroxy-IQ at concentrations which appear to selectively inhibit only bacterial sulfotransferase. The data suggest that bacterial O-acetyltransferase rather than sulfotransferase mutagenically activates N-hydroxy-IQ. N-hydroxy-IQ covalently bound to calf thymus DNA in vitro under non-enzymatic conditions at pH 7.4. Rat hepatic cytosolic O-acetyltransferase and sulfotransferase enhanced the covalent binding of N-hydroxy-IQ to DNA 30- and 5-fold respectively. The data suggest that the mutagenicity of N-hydroxy-IQ is due to the reactivity of N-hydroxy-IQ with DNA and the ability of N-hydroxy-IQ to be further activated by bacterial O-acetyltransferase.
Carcinogenesis 1988 Mar
PMID:Mutagenicity and in vitro covalent DNA binding of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline. 316 8

The mutagenicity of hexachloro-1,3-butadiene and its S-conjugates 1-(glutathion-S-yl)-1,2,3,4,4-pentachloro-1,3-butadiene (GTB), 1,4-(bis-glutathion-S-yl-1,2,3,4-tetrachloro-1,3-butadiene (BGTB) and 1,4-(bis-cystein-S-yl)-1,2,3,4-tetrachloro-1,3-butadiene (BCTB) was investigated in Salmonella typhimurium TA100 using a modified preincubation assay. GTB was a direct-acting mutagen; the mutagenic potency of GTB was markedly enhanced by rat kidney microsomes or mitochondria and less so by cytosol. The bis-conjugates BGTB and BCTB were not mutagenic in the strains TA100, TA2638 and TA98. Purified HCBD was not mutagenic either without exogenous metabolic activation or with rat liver microsomes fortified with NADPH. Preincubation with rat liver microsomes and glutathione resulted in an unequivocal mutagenic activity of HCBD which was increased by additional inclusion of rat kidney microsomes. The cysteine conjugate beta-lyase inhibitor aminooxyacetic acid decreased the mutagenicity of HCBD and its S-conjugates. These results provide strong evidence that formation of the corresponding monoglutathione S-conjugate from HCBD and subsequent cleavage of this conjugate by gamma-glutamyltranspeptidase and beta-lyase may be responsible for the nephrocarcinogenicity of the parent compound in vivo, whereas formation of the bis-glutathione S-conjugate probably plays no role in the organ specific effects of HCBD.
Carcinogenesis 1988 Jun
PMID:Mutagenicity of hexachloro-1,3-butadiene and its S-conjugates in the Ames test--role of activation by the mercapturic acid pathway in its nephrocarcinogenicity. 328 31


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