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)

N-acetylcysteine (NAC) was administered to rats in various combinations with an enzyme inducer (Aroclor 1254) and with depletors of reduced glutathione (GSH), i.e., diethyl maleate (DEM) and buthionine sulfoximine (BSO). NAC increased intracellular glutathione levels in erythrocytes and in liver and lung cells, and replenished its stores following depletion. It did not affect the concentrations nor the spectral properties of cytochromes P-450 in hepatic and pulmonary microsomes, whereas it stimulated, especially in Aroclor-pre-treated animals, cytosolic enzyme activities involved in NADP reduction (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), in glutathione reduction (GSSG-reductase) and in the reductive detoxication of xenobiotics by-passing formation of reactive oxygen species (DT-diaphorase). In vivo treatment with the drug enhanced detoxication by liver and lung S-12 fractions of direct-acting mutagens (ICR 191, epichlorohydrin, 4-nitroquinolino-N-oxide and dichromate) and counteracted opposite effects triggered by administration of GSH depletors. The metabolic activation of procarcinogens (aflatoxin B1, 2-aminofluorene, cyclophosphamide, benzo[a]pyrene, a tryptophan pyrolysate product and cigarette smoke condensate) was inhibited by NAC in uninduced rats, while it was further stimulated in Aroclor-pre-treated animals. Additional assays, performed also with other enzyme inducers (phenobarbital and 3-methylcholanthrene) suggested that the effect of NAC on the metabolic activation of procarcinogens depends on the balance between an increased production of mutagenic metabolites (prevailing in induced animals) and their binding by intracellular thiols (prevailing under normal conditions). Thus, due to its dual role as a nucleophile and as a SH donor, NAC appears to exert protective effects by modulating glutathione metabolism and the biotransformation of mutagenic/carcinogenic compounds. This may have clinical relevance, since NAC is administered to individuals, such as cigarette smokers, who are more heavily exposed to GSH depletors and to carcinogenic agents.
Carcinogenesis 1985 Dec
PMID:In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. 390 42

Histochemical investigation of altered dehydrogenase enzyme activity in putative pre-neoplastic lesions induced by N-ethyl-N-hydroxyethylnitrosamine in the rat liver revealed a clear increase in NADPH-generating potential, most markedly within nodules. Glucose-6-phosphate dehydrogenase, malic enzyme and isocitrate dehydrogenase all showed elevated activity while the activities of succinate dehydrogenase and beta-hydroxybutyrate dehydrogenase were reduced. Alteration in enzyme activity suggested an adaptive shift in metabolism, the increase in levels of enzymes responsible for generation of reduced NADP possibly conferring enhanced drug detoxifying or cholesterogenic potential.
Carcinogenesis 1986 Feb
PMID:Dehydrogenase histochemistry of N-ethyl-N-hydroxyethylnitrosamine-induced focal liver lesions in the rat--increase in NADPH-generating capacity. 394 19

The activities of aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as coenzymes were determined in normal liver, hepatocyte nodules and hepatocellular carcinomas from male Wistar rats. Hepatocyte nodules were produced by intermittent exposure of rats to 0.05% 2-acetylaminofluorene or by initiation with diethylnitrosamine followed by selection using 2 weeks of dietary exposure to 0.02% 2-acetylaminofluorene and partial hepatectomy. The activities of propionaldehyde:NAD and benzaldehyde:NADP aldehyde dehydrogenases were increased in hepatocyte nodules of all types as well as in most hepatocellular carcinomas. The most prominent elevation of enzyme activity was found in the cytosol of persistent hepatocyte nodules (35-60 times) and some hepatocellular carcinomas (92 times) using benzaldehyde and NADP. The benzaldehyde:NADP aldehyde dehydrogenase activity varied considerably between different nodules suggesting the existence of a subpopulation of hepatocyte nodules with very high enzymatic activities. The activity of propionaldehyde:NAD aldehyde dehydrogenase activity as well as of gamma-glutamyltransferase did not show substantial internodular variations. The activity of benzaldehyde:NADP aldehyde dehydrogenase in individual carcinomas investigated in these experiments varied extensively. The data did not support the idea that all hepatomas had been developed from pre-neoplastic nodules with very high activity of this enzyme.
Carcinogenesis 1985 Dec
PMID:Aldehyde dehydrogenase activities in hepatocyte nodules and hepatocellular carcinomas from Wistar rats. 406 45

The resistant hepatocyte model was used to study expression of tumor-associated aldehyde dehydrogenase (ALDH) activity during the course of rat hepatocarcinogenesis. The hepatic ALDH phenotype was determined at intervals over 280 days by histochemical analysis, total ALDH activity assays and gel electrophoresis, using propionaldehyde and NAD (P/NAD) to characterize normal liver ALDH activity or benzaldehyde and NADP (B/NADP) to determine tumor-associated ALDH activity. By total activity assays and gel electrophoresis, no significant changes in ALDH activity occurred until day 70. However, histochemical analysis clearly demonstrated changes in ALDH activity early in neoplastic development. Intense focal hepatocyte staining with P/NAD and/or B/NADP was first detectable at day 28. The number of P/NAD-positive foci increased until day 35 then declined until day 70. The number of B/NADP-positive foci also increased until day 35, but then remained relatively constant for the remainder of the experiment. GGT activity of serial sections indicated that early ALDH-positive lesions represent a small subpopulation (9%) of all GGT-positive foci. However, by day 168 a significant portion (80%) of persistent GGT-positive neoplastic nodules were also B/NADP-positive histochemically. In addition, virtually all hepatocellular carcinomas (96%) generated by this protocol possessed significantly elevated levels of tumor-associated ALDH by histochemical analysis, total ALDH activity and gel electrophoresis. These results indicate that early appearing ALDH-positive lesions may define one early subpopulation of all initiated cells that have a high probability of progressing to the ultimate neoplasm.
Carcinogenesis 1984 Dec
PMID:Expression of tumor-associated aldehyde dehydrogenase during rat hepatocarcinogenesis using the resistant hepatocyte model. 614 20

Several nitroarenes derived from benzo[a]pyrene and perylene and the parent hydrocarbons have been assayed for mutagenicity in the Salmonella microsome test and for affinity for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-receptor protein in rat liver cytosol. 1- and 3-nitrobenzo[a]pyrene are mutagenic in the absence of S9 and have a response pattern in several Salmonella strains resembling that shown by 1-nitropyrene. 6-Nitrobenzo[a]pyrene, 3-nitroperylene as well as the parent unsubstituted hydrocarbons require S9 for activation. The 3,6- and 3,7-dinitroperylenes and a mixture of 3,9-/3,10-dinitroperylene are all mutagenic in the absence of S9. The response pattern of 3,9-/3,10-dinitroperylene resembles that shown by 1,6- and 1,8-dinitropyrenes. The nitro derivatives which are active in the absence of S9 are all inactivated by the addition of an incomplete S9 lacking NADP but activity is regained in the presence of the complete S9 for 1-and 3-nitrobenzo[a]pyrene and 3,6-dinitroperylene, showing that these compounds are also activated by S9 enzymes. Benzo[a]pyrene, 1- and 3-nitrobenzo[a]pyrene, 3-nitroperylene and the mixture of 3,9-/3,10-dinitroperylene have a high affinity for the TCDD-receptor protein whereas the affinity is low or below the detection level for the other compounds. These results are in good agreement with known structural requirements for receptor binding.
Carcinogenesis 1984 Jul
PMID:Short-term bioassays of nitro derivatives of benzo[a]pyrene and perylene. 632 40

N-Acetylcysteine (NAC), reduced (GSH) and oxidized (GSSG) glutathione were negative in the Ames test with 7 Salmonella strains, while L-cysteine was activated by rat liver S-9 fractions to metabolites mutagenic to strains TA102, TA97 and TA100. The mutagenic response in S. typhimurium strains (TA1535, TA98, TA100, TA102) and the levels of enzyme activities, responsible for NADP+ or GSSG reduction and for the utilization of NADPH or GSH in rat liver S-9 fractions, were investigated following in vitro preincubation of NAC with four direct-acting mutagens and six procarcinogens. Treatment with this nucleophilic and reducing compound resulted in a dose-related decrease of the direct mutagenicity of epichlorohydrin, hydrogen peroxide and, sharply, of 4-nitroquinolino-N-oxide and sodium dichromate. The mutagenicity of these compounds, both in the absence and in the presence of NAC, was decreased by rat liver S-9 fractions and to some extent by lung S-9 fractions. A diphasic effect was observed in the case of procarcinogens (cyclophosphamide, 2-aminofluorene, cigarette smoke condensate, Trp-P-2, aflatoxin B1 and benzo[a]pyrene), i.e., an enhancement of S-9 requiring mutagenicity at intermediate NAC doses, which could be ascribed to metabolic factors acting in vitro, and a loss of mutagenicity at high NAC doses, which could be ascribed to trapping of electrophilic metabolites. Out of the five S-9 enzyme activities under study, i.e., glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme, GSH peroxidase and GSSG reductase, only the last one showed significant changes following mutagen and/or NAC treatment.
Carcinogenesis 1984 Apr
PMID:In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens. 636 36

For activation of 2-acetylaminofluorene (AAF) there is an optimal level of rat liver S9 fraction which is considerably lower in the fluctuation test than in the Ames test. The optimal level of S9 is not markedly affected by the dose of AAF used, nor by the ratio of S9 to bacteria, nor by the presence of soft agar. The difference between Ames and fluctuation tests appears to be due to diffusion of some substance or substances from the top agar layer in the Ames test. Diffusion of the co-factors NADP and glucose-6-phosphate is not responsible for the difference in S9 optima, nor is diffusion of soluble S9 constituents although this may considerably affect the performance of the S9 mix. We present evidence that diffusion of non-mutagenic metabolites of AAF from the Ames test top agar may be responsible for the difference in S9 optima. Our results are consistent with a model whereby lipophilic non-mutagenic metabolites accumulate in the microsomes and inhibit further activation. When the metabolites are able to diffuse away, a higher level of S9 will be optimal. The model is consistent with some other phenomena of S9 activation.
Carcinogenesis 1980 Apr
PMID:Optimal levels of S9 fraction in the Ames and fluctuation tests: apparent importance of diffusion of metabolites from top agar. 702 16

In recent years we and others have shown the cancer chemopreventive effects of green tea in several animal tumor models. In this study we assessed the cancer chemopreventive effects of water extract of green tea (WEGT) and the polyphenolic fraction (GTP) isolated from WEGT against N-nitrosodiethylamine (DEN)- and benzo[a]pyrene (BP)-induced forestomach and lung tumorigenesis in A/J mice. The protective effects, both in forestomach and lungs, were evident by a decrease in number of tumors and the percentage of mice with tumors when WEGT and GTP were fed to animals during initiation, post-initiation and entire period of tumorigenesis protocols. Oral feeding of 0.2% GTP in drinking water to mice afforded 68-82 and 39-66% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of pulmonary tumor multiplicity caused by DEN and BP, the protective effects of GTP were between 38-43 and 25-46% respectively. Similarly, oral feeding of 2.5% WEGT to mice also afforded 80-85 and 61-71% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of lung tumorigenesis, the protective effects of WEGT were 43-62 and 25-51% respectively. Histological studies of forestomach tumors showed significantly lower squamous cell carcinoma counts in GTP- and WEGT-fed groups of mice compared to carcinogen alone treated control group of mice. When pulmonary tumors were examined histologically, no adenocarcinomas were observed in GTP- and WEGT-fed groups of mice compared to 20% mice with adenocarcinomas in carcinogen alone treated control group. Oral feeding of GTP and WEGT in drinking water also showed significant enhancement in the activities of glutathione S-transferase and NADP(H): quinone reductase in liver, small bowel, stomach and lung. The results of this study suggest that green tea possesses chemopreventive effects against carcinogen-induced tumorigenesis in internal body organs, and that the mechanism of such effects may involve the enhancement of phase II and anti-oxidant enzyme systems.
Carcinogenesis 1993 May
PMID:Protection against N-nitrosodiethylamine and benzo[a]pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea. 850 76

Ellagic acid is a complex planar molecule which demonstrates a variety of anticarcinogenic activities. Ellagic acid has been shown to inhibit the CYP1A1-dependent activation of benzo[a]pyrene; to bind to and detoxify the diolepoxide of benzo[a]pyrene; to bind to DNA and reduce the formation of O6-methylguanine by methylating carcinogens; and to induce the phase II detoxification enzymes glutathione S-transferase Ya and NAD(P)H:quinone reductase. Chemical analogs of ellagic acid were synthesized to examine the relationship between the hydroxyl and lactone groups of the ellagic acid molecule and its different anticarcinogenic activities. These studies demonstrated that both the 3-hydroxyl and the 4-hydroxyl groups were required for ellagic acid to directly detoxify the diolepoxide of benzo[a]pyrene, while only the 4-hydroxyl groups were necessary for ellagic acid to inhibit CYP1A1-dependent benzo[a]pyrene hydroxylase activity. Induction of glutathione S-transferase Ya and NAD(P):quinone reductase required the lactone groups of ellagic acid, but the hydroxyl groups were not required for the induction of these phase II enzymes. In addition, the lactone groups, but not the hydroxyl groups, were required for the analogs to reduce the carcinogen-induced formation of O6-methylguanine. Thus, different portions of the ellagic acid molecule are responsible for its different putative anticarcinogenic activities.
Carcinogenesis 1996 Feb
PMID:Structure-function relationships of the dietary anticarcinogen ellagic acid. 862 48

Rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD) inactivates circulating steroid hormones and is involved in polycyclic aromatic hydrocarbon (PAH) carcinogenesis. It is the only HSD of known structure in the aldo-keto reductase (AKR) superfamily and may provide a paradigm for other mammalian HSDs in this family. The structure of the 3 alpha-HSD.NADP+ binary complex has been determined at 2.7 A resolution and refined to a crystallographic R-factor of 23.4% with good geometry. The model is similar to other binary complexes in the AKR superfamily in that NADP+ binds at the C-terminal end of an alpha/beta barrel. However, it is unique in that NADP+ is bound in two alternate conformations, probably because of the lack of a salt-linked "safety belt" over the pyrophosphate bridge. The structure supports a previously proposed catalytic mechanism for carbonyl reduction in which Tyr 55 is the general acid, and its effective pKa is lowered by the adjacent Lys 84. We present evidence that the structurally distinct short-chain dehydrogenase/reductase (SDR) superfamily may have convergently evolved a similar catalytic mechanism. Insight into substrate binding is offered by a crystal packing contact in which a neighboring molecule inserts a tryptophan residue (Trp 227) into an apolar cleft in 3 alpha-HSD. This cleft is proximal to the bound NADP+ cofactor and contains a surface of apolar residues (Leu 54, Trp 86, Leu 122, Phe 128, Phe 129, Leu 137, Phe 139), making it a likely candidate for the substrate-binding site. Thus, in forming this crystal contact, Trp 227 may mimic a portion of a bound steroid. In addition, we propose that a water molecule in the active site indicates the position of the hydroxyl oxygen in a 3 alpha-hydroxysteroid substrate. Knowledge of the position of this water molecule, combined with the stereochemistry of hydride transfer, suggests that the alpha face of a bound steroid will be oriented toward the side of the apolar cleft containing Trp 86.
 ...
PMID:Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+. 871 59


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