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

The distribution of 4-nitroquinoline 1-oxide (4-NQO) reductase, assumed to be closely related to the carcinogenesis of 4-NQO, was investigated in the mucosa of canine digestive tract, and its results indicated following points. 1) The activity of 4-NQO reductase was highest in the esophagus, next in the stomach, and remarkably low in the small and large intestines. 2) There is no significant difference in the 4-NQO reductase activity between the upper, middle, and lower portion of the esophagus, but its activity was higher in the female than in the male in its upper and middle portions. 3) Among the esophageal tissue, its activity was high only in the mucous epithelium and very low in all other layers. 4) Most of the enzymic activity in the esophageal mucosa existed in the cytosol fraction and activity of the microsome fraction was remarkably low. Even if NADPH or NADH was used as the hydrogen donor, its activity was not different in the cytosol fraction, but the former was a better hydrogen donor in the microsome fraction. 5) In the gastric mucosa, the enzymic activity was equally high in various portions of the corpus ventriculi; the greater and lesser curvatures, anterior and posterior parietes, and fundus. It was remarkably low only in the pyloric antrum.
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PMID:Distribution of 4-nitroquinoline 1-oxide reductase in the mucosa of canine digestive tract. 9 82

The previously observed alterations in the energy transducing system of rat liver mitochondria during 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) carcinogenesis were investigated using aliphatic dicarbonyl compounds as molecular probes and the effect of temperature on the membrane-linked NADH-indophenol reductase. The vicinal diketone, diacetyl, uncouples oxidative phosphorylation in normal rat liver mitochondria while the higher diketones, acetylacetone and acetonylacetone, are increasingly less effective in that order; diacetyl totally abolishes respiratory control with substrates the oxidation of which involves the NADH leads to CoQ segment, but only partially with succinate which bypasses this segment. Diacetyl, likewise, uncouples oxidative phosphorylation in liver mitochondria from rats fed 3'-Me-DAB, but the mitochondria are most resistant to this uncoupling (in terms of the P/O ratio) at the time period when the respiratory control index (determined in the absence of diacetyl) is at the dye-induced minmum. This time period is at 3 to 4 weeks of dye administration, representing the cumulative dose for tumorigenesis threshold. At this threshold period of feeding 3'-Me-DAB, discontinuities in the Arrhenius plot of the mitochondrial membrane-localized NADH-indophenol reductase appear, with a return toward the control state (no break) at 8 weeks, only to reappear in the plot of the enzyme from tumor mitochondria, suggesting sequential membrane phase transitions in the mitochondria during azo dye carcinogenesis.
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PMID:Mitochondrial membrane-linked reactions in carcinogenesis: change in steroselective uncoupling of oxidative phosphorylation by aliphatic dicarbonyls and in the Arrhenius plot of NADH-indophenol reductase. 40 68

Incubation of rat liver cytosolic or microsomal fractions with chromium(VI) led to a dramatic decrease in chromium(VI) mutagenicity, as determined by the Ames Salmonella assay using the TA100 tester strain. The cytosol-dependent decrease in chromium(VI) mutagenicity was found to be counteracted in the presence of dicumarol, an inhibitor of the cytosolic enzyme NAD(P)H:quinone oxidoreductase (DT-diaphorase). In order to determine whether DT-diaphorase is a significant factor in enzymatic reduction of chromium(VI) in rat liver tissue, cytosolic and microsomal fractions were analyzed for NAD(P)H-dependent chromium (VI) reductase activity leading to chromium(V) formation by using electron paramagnetic resonance (EPR) spectroscopy. Reaction of chromium(VI) with NADH or NADPH in the presence of either cytosolic or microsomal fractions led to the formation of stable chromium(V)--NAD(P)H complexes. When glucose 6-phosphate (G6P) was present in the reaction as part of a NADPH-generating system, stable chromium(V)--G6P complexes were formed in addition to the chromium(V)--NAD(P)H complexes. The chromium(V) complexes had g values of 1.980-1.982 and superhyperfine splitting constants of 0.8-0.9 characteristic of bis(diol)oxochromium(V) complexes. Inhibition of 90% of the cytosolic DT-diaphorase activity by dicumarol led to only partial (20-22%) inhibition of chromium(V) formation. Visible and EPR spectroscopic studies showed that purified DT-diaphorase had no detectable chromium(VI) reductase activity and did not catalyze formation of chromium(V). Inhibition of 69% of microsomal aryl hydrocarbon hydroxylase activity by ketoconazole led to partial (10%) inhibition of chromium(V) formation. These results indicate that intracellular NAD(P)H-dependent enzymatic reduction of chromium(VI) in rat liver cannot be attributed to the activity of any one enzyme in the cytosolic or microsomal fractions. DT-diaphorase appears to play an indirect role in decreasing chromium(VI)-induced mutagenicity in Salmonella, possibly through interaction with other redox active cellular components. The involvement of diols such as sugars and pyridine nucleotides in stabilizing intracellularly generated chromium(V) is discussed.
Carcinogenesis 1992 Jul
PMID:Reduction of chromium(VI) to chromium(V) by rat liver cytosolic and microsomal fractions: is DT-diaphorase involved? 137 26

Peroxidase in the presence of hydrogen peroxide catalyzes in vitro the activation of carcinogenic N,N-dimethyl-4-aminoazobenzene (DAB) to DNA-, tRNA- and homopolydeoxyribonucleotide-bound products. tRNA is the most susceptible to modification by the activated DAB. Binding of DAB products to macromolecules is inhibited by methyl viologen, nitrosobenzene, ascorbate, glutathione, NADH and MgCl2. The mechanism of these inhibitions was studied. The nuclease P1 version of the 32P-postlabeling assay was employed for detection and quantitation of some major DNA or tRNA adducts formed with DAB activated by a peroxidase system. tRNA modified by activated DAB shows a significantly increased acceptance for L-methionine.
Carcinogenesis 1992 Sep
PMID:Formation and 32P-postlabeling of DNA and tRNA adducts derived from peroxidative activation of carcinogenic azo dye N,N-dimethyl-4-aminoazobenzene. 139 52

The significance of the nonspecific esterases of human mononuclear leukocytes (HMLs) in arylamine carcinogenesis is suggested by data showing that the metabolically formed hydroxamic acid derivative of 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, is a substrate for this class of enzymes. A viable cell assay for the nonspecific esterases using alpha-naphthyl acetate as substrate is described, and data showing this activity to be sensitive to already known substrates for HML esterases as measured by three previously described assays are presented. All four assays of the same esterase activity are shown to be highly sensitive to up- and down-regulation by addition of NADPH or NADP to viable HML cultures. Selective activation of a purified rabbit nonspecific esterase by NADPH, but not by the other cellular reductants, NADH and glutathione, was demonstrated. Cytosols prepared from normal human tissue samples of liver, breast, colon, and brain were also activated by the presence of NADPH. These data do not indicate that steroidal nonspecific esterases are redox-modulated by the presence of mixed disulfides in their structure. Instead, they support the direct and specific influence of NADPH as a widespread activator of esterase activity by a mechanism not yet understood.
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PMID:Steroidal nonspecific esterase metabolism of N-hydroxy-2-acetylaminofluorene: evidence for selective activation by the cellular reductant NADPH. 143 49

Dinitropyrenes (DNP) are potent bacterial mutagens in the Ames test and genotoxins in cultured mammalian cells. Rat liver cytosol contains nitroreductases that are critical in the activation of DNP to the ultimate DNA-binding species. In order to study the nature and inducibility of liver cytosolic enzymes involved in the activation of DNP, cytosolic nitroreductase activities towards three DNP isomers (1,3-, 1.6- and 1,8-DNP) were determined in Aroclor-pretreated and untreated rats. Aroclor-1254 pretreatment resulted in up to 5-fold induction of cytosolic DNP nitroreductase. This induction was reflected in at least a 15-fold increase in cytosolic NAD(P)H-quinone oxidoreductase (NQOR) (E.C. 1.6.99.2) activity. The rates of nitroreduction for the three DNP isomers followed the order 1,6- greater than 1,8- greater than 1,3-DNP in all cases studied. 1,6-DNP nitroreductase coeluted with NQOR activity upon affinity purification. Highly purified NQOR catalyzed the NADH- and NADPH-dependent reduction of each of the three DNP isomers and displayed the same stereospecificity as the cytosolic activity. These results provide evidence that NQOR participates in the cytosolic nitroreduction of DNP and constitutes a major part of the total DNP nitroreductase activity upon induction of NQOR by Aroclor-1254 pretreatment. Thus, the role of NQOR in the metabolism of these mutagens depends significantly upon the degree to which this enzyme is induced.
Carcinogenesis 1991 Apr
PMID:Dinitropyrene nitroreductase activity of purified NAD(P)H-quinone oxidoreductase: role in rat liver cytosol and induction by Aroclor-1254 pretreatment. 190 25

Topical application on rat oral mucosa of the chemical 4-nitroquinoline 1-oxide (4NQO) has been shown to produce squamous cell carcinomas on the posterior tongue and/or the posterior hard palate. 4NQO is broken down in vivo by a diaphorase, 4NQO reductase (E.C.1.6.99.2), to produce an active molecule believed to be responsible for carcinogenesis. It has been shown that there are higher concentrations of 4NQO reductase in oesophageal mucosa compared with elsewhere in the gastrointestinal tract. The purpose of these experiments was to compare the distribution of certain diaphorases in the oral mucosa. Samples of rat tongue and cheek epithelia were homogenized, then ultracentrifuged to provide mixed cytosol and microsome fractions from the epithelial cells. A spectrophotometer was used to measure the variation in absorbance at 340 nm of NADH consumed by reduction of 4NQO by enzymes present in the tissue extracts. A histochemical technique was used to compare the activity of NADH diaphorase, NADP diaphorase and glucose-6-phosphate dehydrogenase at different sites of the oral mucosa. Statistical analysis showed that there were significant (P less than 0.01) differences between the activities of all three enzymes at different sites of the oral mucosa. In each case, a higher activity was found at the sites of high incidence of squamous cell carcinoma. A lower activity was found at sites where carcinomas did not occur.
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PMID:A relationship found between intra-oral sites of 4NQO reductase activity and chemical carcinogenesis. 211 96

A novel route for the microsomal generation of nitrogen mustard from its N-oxide nitromin is demonstrated. The mustard was trapped as an adduct with diethyldithiocarbamate and estimated by capillary GLC. The enzyme responsible for this reduction could utilize either NADPH or NADH. Reduction occurred preferentially under anaerobic conditions. Purified cytochrome P450 reductase could carry out this reaction. Similar activities were seen using microsomal fractions from rat liver or liver derived BL8, JB1 or Walker 256 carcinoma cells, when these were expressed on a per mg of protein basis. Unscheduled DNA synthesis (UDS) was used as an index of activation of nitromin in these cell systems. In all instances, greater induction of UDS occurred in cells incubated with nitromin under anaerobic conditions.
Carcinogenesis 1989 Nov
PMID:Reduction of nitromin to nitrogen mustard: unscheduled DNA synthesis in aerobic or anaerobic rat hepatocytes, JB1, BL8 and Walker carcinoma cell lines. 250 92

Incubation of chromate with isolated rat liver submitochondrial particles under anaerobic conditions in vitro results in reduction of chromium(VI) and formation of chromium(V). In the presence of NADH, submitochondrial particles (SMPs) were active in reducing chromate as shown by UV-vis spectroscopic studies, and forming a chromium(V) species which was detectable by electron paramagnetic resonance spectroscopy. In the presence of succinate, SMPs were less effective in reducing chromate and forming chromium(V) relative to their NADH-dependent activity. However, SMPs showed a higher rate of oxygen depletion with NADH as compared to succinate as substrate, suggesting that differences in the NADH-dependent versus succinate-dependent chromate-reductase activity of SMPs is probably due to differences in efficiency of electron donation by succinate and NADH. The use of specific electron transport chain inhibitors allowed the sites of chromium(VI) reduction and chromium(V) formation in SMPs to be determined. Rotenone, antimycin and cyanide all produced approximately 40% inhibition of the NADH-dependent chromate-reductase activity. Thus, complex I (NADH:ubiquinone oxidoreductase) appears to be responsible for the inhibitor-insensitive, and complex IV (ferrocytochrome c:oxygen oxidoreductase) for the inhibitor-sensitive NADH-dependent chromium(VI) reduction and chromium(V) formation. Cyanide and antimycin produced approximately 50% inhibition of the succinate-dependent chromate-reductase activity of SMPs, while no detectable inhibition was observed with rotenone. These results confirm the chromate-reductase activity of complex IV, and suggest that complex II (succinate:ubiquinone oxidoreductase) is responsible for the inhibitor-insensitive succinate-dependent chromate-reductase activity of SMPs. Since chromium(VI) is effectively metabolized by electron transport chain complexes of the mitochondrial inner membrane in vitro, and chromium(V) is formed as an intermediate in the process, mitochondria may play a role in chromium(VI) carcinogenesis.
Carcinogenesis 1989 May
PMID:Chromium(V) is produced upon reduction of chromate by mitochondrial electron transport chain complexes. 253 17

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
Carcinogenesis 1989 Jun
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3


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