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

Several studies have indicated a correlation between the presence of inflammation and the development of cancer. The aim of our study was to determine if pulmonary neutrophils could transform the proximate respiratory carcinogen (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol), to an ultimate carcinogenic metabolite via myeloperoxidase (MPO). To test this hypothesis, virus-free male DBA/2 mice were exposed by inhalation to the Gram-negative bacteria Proteus mirabilis for 1 h. For various time points post-exposure, bronchoalveolar lavage (BAL) was performed to determine total and differential cell counts, cellular MPO activity and production of superoxide. Twelve hours after the exposure, cellular activity of MPO as well as percentage and total number of polymorphonuclear leukocytes peaked and declined thereafter. At this same time point, cells from BAL exhibited increased release of superoxide, as measured by reduction of cytochrome c, after addition of soluble or particulate stimuli, 12-O-tetradecanoylphorbol-13-acetate (TPA) or opsonized zymosan respectively. These cells also elicited biotransformation of B[a]P-7,8-diol as evidenced by enhanced B[a]P-7,8-diol-derived chemiluminescence, tetraol formation and covalently bound adduct formation to exogenous DNA upon addition of TPA or opsonized zymosan. Moreover, the cell-free BAL fluid of infected mice contained substantial MPO activity in comparison to that of uninfected animals. Also, MPO enhanced the binding of B[a]P-7,8-diol to lung DNA in vitro. Unlike previous work emphasizing the potential roles of oxygen free radicals in tumor promotion, our results indicate a role of neutrophilic MPO in the initiation of carcinogenesis.
Carcinogenesis 1992 Jul
PMID:Myeloperoxidase-enhanced formation of (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene-DNA adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen. 132 50

Nitrofluoranthenes (NFs) are mutagenic and carcinogenic environmental pollutants found in incomplete combustion products and urban air particulate. We have studied both oxidative and reductive metabolism in vitro of different NF isomers mediated by subcellular rat liver fractions. Under aerobic conditions only ring hydroxylation of NFs by rat liver microsomes occurred and the isomeric position of the nitro group affected both the amount and the type of phenolic metabolites formed. Liver microsomes from 3-methylcholanthrene-induced rats were most effective in giving ring hydroxylated 7- and 8-nitrofluoranthene, whereas liver microsomes from phenobarbital-pretreated rats were the most active in metabolizing 1- and 3-nitrofluoranthene. Under anaerobic conditions, only reduction of NFs mediated by both cytosolic and microsomal rat liver enzymes occurred. Cofactor requirements and inhibition experiments indicated that the reductase activity in rat liver cytosolic fractions could be ascribed to DT-diaphorase, aldehyde oxidase and/or other unknown enzymes. The microsomal reductase activity was inhibited by oxygen, carbon monoxide, 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride and n-octylamine, and slightly by cytochrome c; flavin mononucleotide greatly enhanced this activity. 3-Nitrofluoranthene microsomal nitroreductase activity was increased by phenobarbital rat pretreatment and this increment correlated well with the content of cytochrome P450. These results indicate a participation of cytochrome P450 in the reductive metabolism of NFs by rat liver microsomes.
Carcinogenesis 1990 Feb
PMID:Characterization of oxidative and reductive metabolism in vitro of nitrofluoranthenes by rat liver enzymes. 230 47

The role of arachidonic acid (AA) metabolism in the stimulation of oxygen radical production by murine peritoneal macrophages treated with tumor promoters was assessed. In vivo administration of the phospholipase A2 inhibitor dibromacetophenone, the anti-inflammatory steroid fluocinolone acetonide or the lipoxygenase inhibitor nordihydroguiaretic acid just prior to i.p. injection of phorbol-12-myristate-13-acetate (PMA, 100 ng) into unmanipulated CD-1 female mice resulted in a dose-dependent decrease in the number of peritoneal exudate cells (PEC) producing superoxide anion radical (O2) as assessed by the reduction of nitroblue tetrazolium, i.e. the formation of formazan-positive PEC. The cycloxygenase inhibitor indomethacin had no effect on the number of formazan-positive PEC caused by PMA treatment. The ability of PMA, phorbol-12,13-dibutyrate mezerein, phorbol-12,13-diacetate and 4-O-Me-PMA to stimulate the production of oxygen radicals by murine peritoneal macrophages correlated with their ability to stimulate the release of [3H]AA equivalents from the macrophages. The calcium ionophore A23187 which stimulated significant [3H]AA equivalent release did not stimulate superoxide anion radical production by the macrophages. PMA administered i.p. to SENCAR mice increased the number of formazan-positive PEC 4-to 5-fold compared with similarly treated C57BL/6 mice. PMA also stimulated the release of twice the amount of [3H]AA equivalents from peritoneal macrophages from SENCAR mice compared with that released by macrophages from C57BL/6 mice. The addition of low concentrations of AA (1-10 microM) in vitro to casein-elicited murine peritoneal macrophages treated with low concentrations of PMA (1 ng/ml) resulted in a 2-fold potentiation of the amount of superoxide anion radical produced compared with PMA treatment alone as assessed by the reduction of cytochrome c. These results demonstrate that AA and/or a lipoxygenase product can potentiate the production of oxygen radicals by murine peritoneal macrophages treated with tumor promoters.
Carcinogenesis 1989 Oct
PMID:Arachidonic acid potentiates superoxide anion radical production by murine peritoneal macrophages stimulated with tumor promoters. 255 22

We have found that activated resident peritoneal macrophages from Wistar-Furth and Sprague-Dawley rats produce significantly more superoxide (2.2 +/- 0.4 and 3.6 +/- 0.8 nmol of cytochrome c reduced/10(6) cells/10 min respectively) than those from Lewis rats (1.0 +/- 0.3 nmol of cytochrome c reduced/10(6) cells/10 min). Similar results are found in macrophages elicited with intraperitoneal thioglycolate. Furthermore, nitrate excreted in the urine increased greatly when either Wistar-Furth or Sprague-Dawley rats are injected i.p. with iota carrageenan (0.25 g), a response that did not occur with Lewis rats. This strain difference in the manifestations of the inflammatory response correlates with previous observations that Wistar-Furth and Sprague-Dawley rats, but not Lewis rats, develop suture-line colonic tumors when the ureters and bladder base are implanted into the colon.
Carcinogenesis 1988 Apr
PMID:Nitrate production and phagocyte activation: differences among Sprague-Dawley, Wistar-Furth and Lewis rats. 283 68

Retinol and retinoic acid were effective activators of oxygen consumption by human polymorphonuclear leucocytes (PMN) in micromolar concentrations. In contrast, retinyl acetate was ineffective as an activator. Retinol caused activation only after a lag time, the length of which depended on retinol concentration. Oxygen consumption was due to superoxide production by PMN. Superoxide production was observed as superoxide dismutase-inhibitable cytochrome c reduction. Previously, retinoids have been reported to inhibit PMN activation by phorbol myristate acetate, a tumour promoter. This retinoid-induced inhibition of PMN activation has been suggested to be a mechanism by which retinoids may protect against carcinogenesis in animals. However, the retinoid concentrations at which PMN inhibition was reported were much higher than those found to cause activation in this study. We found that retinoic acid slightly inhibited phorbol myristate acetate-activated superoxide production, but only at concentrations that caused activation. In contrast, activation by formyl-Met-Leu-Phe was effectively inhibited at a retinoic acid concentration that did not cause activation by itself.
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PMID:Retinoids activate superoxide production by polymorphonuclear leucocytes. 298 77

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

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

The mutagenic potential of nine carcinogenic N-nitrosopropylamines was examined by Ames preincubation assay using liver 9000 g supernatant (S9) fractions from female rats and male hamsters and mice for metabolic activation. N-Nitrosobis(2-hydroxypropyl)amine, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-oxopropyl)amine, N-nitrosobis(2-acetoxypropyl)amine, N-nitroso-2,6-dimethylmorpholine, N-nitrosomethyl(2-hydroxypropyl)amine, N-nitrosomethyl(2-oxopropyl)amine, N-nitroso(2,3-dihydroxypropyl)(2-hydroxypropyl)amine and N-nitrosomethyl(2,3-dihydroxypropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 from three animal species pretreated with polychlorinated biphenyls or phenobarbital (PB). The S9-mediated mutagenicity of these N-nitrosamines was almost completely diminished by the removal of NADP+ from the assay system. All the activities were considerably decreased by preincubation in an atmosphere of carbon monoxide or adding cytochrome c to the S9 mixture. Metyrapone considerably inhibited mutagenicity, whereas 7,8-benzoflavone was totally lacking this effect. These results demonstrate a correlation between the mutagenicity of nine N-nitrosopropylamines mediated by liver S9 from three animal species and their known carcinogenicity in rodent in vivo experiments, and that the PB-inducible major cytochrome P-450 is selectively involved in the mutagenic activation. A relationship between mutagenic potencies of the N-nitrosamines and their known carcinogenic potencies in rats and hamsters is discussed.
Carcinogenesis 1986 Mar
PMID:Mutagenic activation of carcinogenic N-nitrosopropylamines by liver S9 fractions from mice, rats and hamsters: evidence for a cytochrome P-450-dependent reaction. 351 16

Water solubility and non-toxic properties of ascorbic acid are taken as criteria for beneficial effects of large doses of the vitamin. In the present study, male guinea pigs, dosed daily with 15, 30 or 50 mg/100g body weight for 10 weeks, demonstrated no differences in effect on liver and lung weights, body growth and microsomal protein contents of liver and lung when compared with controls. When guinea pigs were fed excessive ascorbic acid, there was a small non-significant increase (p less than 0.05) in hepatic and pulmonary cytochrome P-450, and significant increase (p less than 0.05) in hepatic cytochrome b5 which was accompanied with a significant increase in arylhydrocarbon hydroxylase activity in the two organs. Activity of NADPH-dependent cytochrome c-reductase was decreased in liver and remained unaffected in lung and colon. Drug detoxifying enzymes responded in different ways to increased intake of ascorbic acid. Activity of UDP-glucuronyltransferase remained unchanged on feeding excessive ascorbic acid, whereas glutathione S-transferase was decreased significantly in liver and was unaltered in lung and colon. Reduced glutathione was decreased only in the lung. The observed changes in drug activating and detoxifying enzymes appear to be important from drug pharmacokinetics and carcinogenesis point of view.
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PMID:Effect of large doses of ascorbic acid on the hepatic and extra-hepatic drug-metabolizing enzymes in guinea pig. 380 Oct 39

Mutagenic potential of carcinogenic N-nitrosopropylamines was examined by the Ames's liquid incubation assay, using rat liver 9000 g supernatant (S9) fraction for metabolic activation. N-Nitrosobis(2-hydroxypropyl)amine, N-nitroso(2-hydroxypropyl)-(2-oxopropyl)amine (HPOP), N-nitrosobis(2-oxopropyl)amine (BOP), N-nitrosobis(2-acetoxypropyl)amine, N-nitroso-2,6-dimethylmorpholine, N-nitrosomethyl-(2-hydroxypropyl)amine and N-nitrosomethyl(2-oxopropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 while being negative in strain TA98. With the exception of HPOP and BOP, which were also mutagenic in TA100 without S9 metabolic activation, these N-nitrosopropylamines required the presence of microsomes as a source of enzymes as well as NADP+ as a cofactor for mutagenic activation. Treatment of rats with polychlorinated biphenyls or phenobarbital (PB) resulted in a marked increase in the ability of S9 to activate the seven N-nitrosamines tested whereas 3-methylcholanthrene (3-MC) induction was not effective. All the mutagenic activities were considerably decreased by preincubation in an atmosphere of either carbon monoxide or nitrogen gas or by adding cytochrome c to the S9 mixture. Metyrapone, a specific inhibitor of PB-inducible major cytochrome P-450, considerably inhibited mutagenicity, whereas 7,8-benzoflavone, a specific inhibitor of 3-MC-inducible major cytochrome P-448, was totally lacking this effect. These results demonstrate a correlation between rat liver S9 dependent mutagenicity of six N-nitrosopropylamines and their known carcinogenicity in rat in vivo experiments, and that the PB-inducible major cytochrome P-450 is involved in the mutagenic activation. BOP was also shown to be activated by extrahepatic (lung, kidney, pancreas) tissue S9, blood S9 and bovine serum albumin (BSA) to the extent of 50% of that activity obtained with liver S9. A possible mechanism of BSA-mediated activation of BOP is discussed.
Carcinogenesis 1985 Mar
PMID:Mutagenic activation of carcinogenic N-nitrosopropylamines by rat liver: evidence for a cytochrome P-450 dependent reaction. 388 71


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