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)

Administration of the nephrotoxicant mercuric chloride (HgCl2) was found to increase microsomal epoxide hydrolase (EH) activity in the kidneys of Fischer 344 (F344) and Sprague-Dawley (SD) rats, but the increases observed were 2- to 4-fold greater in SD rats than in F344 rats. This study was designed to characterize HgCl2-mediated increases in renal EH activity, and to investigate possible biochemical mechanisms underlying the strain difference. In male SD rats killed 24 h after the last of three daily i.p. injections of HgCl2 (0.1-1 mg/kg), increases in renal EH activity were dose dependent, reaching a maximum of 550% of control. Renal EH activities in identically treated F344 rats were enhanced only to 200% of control values, however, the extent of nephrotoxicity was similar in both strains. Following a single HgCl2 treatment (1 mg/kg), maximal increases in renal EH activities were observed in SD rats (450% of control) at 3 days, and in F344 rats (225%) at 1-2 days. Hepatic glutathione (GSH) concentrations were unaffected by HgCl2 treatment, whereas renal GSH was slightly elevated in both strains. Hepatic metallothionein (MT) concentrations were increased at 1 day to 300% and 400% of control in F344 and SD rats, respectively. Maximal renal MT concentrations were observed at 2 and 3 days in F344 (300% of control) and SD (225%) rats, respectively. Pretreatment with Zn(OAc)2, a potent inducer of renal and hepatic MT, reduced the nephrotoxicity of HgCl2, but did not alter HgCl2-mediated renal EH increases in either strain. In addition, possible strain differences in 203HgCl2 distribution were assessed, but 203Hg distribution was similar in both strains. These studies have demonstrated that renal EH activity is induced by HgCl2, and that there is a strain difference in this response. Differences in MT, GSH and organ distribution of Hg do not account for the strain difference. The possibility remains that other, yet to be defined, protection pathways may exist. Alternatively, renal EH may be differentially regulated between the two strains.
Carcinogenesis 1988 Feb
PMID:Strain difference in rat renal microsomal epoxide hydrolase elevation after mercuric chloride treatment. 333 2

Intraperitoneal injection of ethionine to male rats for up to 12 days caused a pronounced fall in S-adenosylmethionine (AdoMet) in liver, but did not or only slightly affect AdoMet in kidney and spleen. Liver and to a lesser degree kidney showed a dose-dependent, massive accumulation of the metabolic product, S-adenosylethionine (AdoEth), and this metabolic response was most pronounced within the first days of exposure. Trace amounts of AdoEth was demonstrated in the spleen. Both S-adenosylhomocysteine (AdoHcy) and homocysteine (Hcy) in the liver were markedly increased in a dose- and time-dependent manner. There was a moderate increase in Hcy content in spleen and kidney, whereas the AdoHcy levels in these tissues were not affected. The amount of reduced glutathione (GSH) was significantly increased in liver and kidney. This response in liver was evident within 2 days of ethionine exposure and then leveled off whereas there was a gradual increase in GSH in kidney. The GSH content in spleen was unaltered. In addition to a massive build-up of AdoEth, the unique features of the metabolic response of the liver are a pronounced decrease in the AdoMet/AdoHcy ratio (from 15 to 2) associated with an elevated Hcy content and a rapid increase in the amount of GSH. The possibility that the metabolic response of the liver could be assigned to the existence of isozymes or metabolic pathways unique to hepatic cells is discussed.
Carcinogenesis 1988 Feb
PMID:Differential metabolic response of rat liver, kidney and spleen to ethionine exposure. S-adenosylamino acids, homocysteine and reduced glutathione in tissues. 333 5

The mucosal glutathione content of the gastrointestinal wall amounted to 50-60% of its concentration in the liver. GSH S-aryltransferase activity (CDNB) was very low in the glandular stomach, colon and rectum amounting to only 5% of liver enzyme activity. There was a marked postpyloric increase in GSH S-aryltransferase activity with an oral-aboral decline along the small intestine. GSH peroxidase was much lower in the mucosa of the small and large intestine as compared to the stomach or liver, whereas GSSG reductase was more than twice as high in the gastrointestinal mucosa as compared to the liver showing a gradual increase in activity from proximal to distal segments. The low GSH S-transferase activities found in the stomach, colon and rectum may account for the high and exclusive susceptibility of these segments to carcinogenesis and the deficient inducibility of these enzymes in the gastrointestinal wall may reflect an insufficient adaption towards higher exposure to toxic or even carcinogenic xenobiotics.
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PMID:Glutathione and GSH-dependent enzymes in the gastrointestinal mucosa of the rat. 337 Jun 30

In the present studies we have compared the levels of glutathione (GSH) and GSH-related enzymes in lung tumors and corresponding normal tissues obtained from the same individuals. We have also immunologically quantitated the relative amounts of glutathione S-transferase pi (or GST-P) type antigen in tumors and adjacent normal tissues from five patients. GST activities towards 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid were found to be elevated in tumors from two out of five patients (patients #1 and 4), whereas the activity towards these substrates was markedly suppressed in the tumor tissue from one of the patients (#5). Immunotitration and Western blot studies using antibodies raised against pi-type GST isoenzymes of human lung and placenta indicated induction of GST pi-type isoenzyme in tumors from patients #1 and 4 and suppression of this isoenzyme in tumor from patient #5. The tumors from patients #2 and 3 did not show any increase in GST activity or GST pi-type antigen. Except for the tumor from patient #5, the GSH content was higher in the tumors from other patients. GSH reductase activity was found to be elevated in tumors of all the patients examined in this study. These results indicate that GSH and GSH related enzymes are differentially altered in lung tumors and GSH levels and GST pi- or GST-P-type isoenzyme(s) are not uniformly elevated in all tumors.
Carcinogenesis 1988 Sep
PMID:Glutathione S-transferase isoenzymes in human lung tumors. 340 73

The changes in the hepatic drug metabolizing enzymes induced by the liver tumor promoter thiobenzamide (TB) were investigated. Feeding of TB to rats at a promoting regimen (1 g/kg of diet for 2 weeks) resulted in a significant decrease in the amount of liver microsomal cytochrome P-450 and of total heme. Also, the activity of cytochrome P-450 dependent monooxygenases (aminopyrine demethylase, arylhydrocarbonmonooxygenase and ethoxycoumarindeethylase) and FAD-containing monoxygenase (N,N-dimethylaniline N-oxidase and TB S-oxidase) were depressed. By contrast, phase II enzymes such as epoxide hydrase, UDP-glucuronyl transferase and GSH-transferase were significantly induced. This overall change in the drug metabolizing system was associated with tolerance of the liver towards a high necrogenic dose of TB itself as well as with an increase of mitoses and apoptosis of the hepatocytes. The findings suggest a possible relationship between this TB-induced adaptive response and the promoting activity of the compound on liver carcinogenesis.
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PMID:Changes in the rat liver drug metabolizing system during a short thiobenzamide feeding cycle. 343 87

The study was aimed at determining the role of glutathione (GSH) conjugation in the binding of reactive benzo[a]pyrene (BaP) species to DNA of C3H/10T1/2 cells. In order to suppress GSH conjugation cells were depleted of GSH by treatment with buthionine sulfoximine for 18 h and 1-chloro-2,4-dinitrobenzene for 1 h prior to incubation with radiolabelled substrates. Under these conditions GSH levels decreased to less than 1% of the control value. C3H/10T1/2 cells produced GSH conjugates with 7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaPDE) comprising 6% of the total metabolites formed from BaP or (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BaP-7,8-diol). In GSH-depleted cells formation of GSH conjugates with metabolic products of BaP or BaP-7,8-diol was suppressed to 1% of total metabolites during an 8-h incubation period. Metabolic activation of BaP and BaP-7,8-diol by C3H/10T1/2 cells resulted in the formation of DNA adducts which largely consisted of BaPDE:deoxyguanosine. Depletion of GSH altered neither the degree of DNA binding nor the pattern of DNA adducts to any significant extent. When C3H/10T1/2 cells were co-incubated with microsomes from liver of 3-methylcholanthrene-treated rats for 1 h in order to activate BaP or BaP-7,8-diol extracellularly, the same pattern of GSH conjugates and DNA adducts was generated as by intracellular metabolism of the polycyclic hydrocarbons. No GSH conjugates were detected following co-incubation of microsomes with GSH-depleted C3H/10T1/2 cells. The formation of DNA adducts again remained unaffected by the suppression of conjugation. C3H/10T1/2 cells are apparently capable of conjugating BaPDE with GSH but are not capable of trapping by GSH conjugation those BaPDE moieties which bind to DNA. The results are compatible with the notion that BaPDE is partially contained in a cellular compartment--presumably the lipid environment of membranes--where it is inaccessible to GSH transferases of C3H/10T1/2 cells.
Carcinogenesis 1987 Aug
PMID:Glutathione depletion suppresses conjugation of benzo[a]pyrene metabolites and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene metabolites with glutathione but does not affect their binding to DNA in C3H/10T1/2 mouse fibroblasts. 360 89

Carcinogenic xenobiotics can be detoxified by nucleophilic thiols, which interact directly or through enzyme catalyzed reactions with electrophilic metabolites/compounds or metabolically produced oxidants. Formation of such conjugates is assumed to be a dominating competitive pathway reducing the mutagenic and carcinogenic effects of several known carcinogens. In the case of the potent carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) the situation is different since this carcinogen is transformed to reactive intermediates by nucleophilic agents such as thiols. As a consequence of this, the modulating effect of thiols has to be discussed in relation to the reaction kinetics of this nitroso compound. In this report we present data on the mutagenicity of MNNG which was enhanced by intracellular excess of glutathione, achieved by pre-treatment with N-acetylcysteine, cysteine and glutathione. Depletion of GSH by treatment with diethylmaleate or buthioninesulfoximine resulted in a decreased mutagenic effect of MNNG. A decreased effect of MNNG was also obtained by extracellular excess of thiols. The modification of MNNG-mutagenicity was compared to the effect of thiols on the mutagenicity of N-methyl-N'-nitrosourea (MNU) in V79 Chinese hamster cells. No effect of the thiols could be detected on the mutagenicity of MNU, indicating that the intermediates of MNU and MNNG react, in agreement with the reaction kinetics, in favour of water and thiols become less important. The results indicate that the activation of MNNG to mutagenic intermediates is occurring within the cells. This activation is mediated by reaction of MNNG with thiols (and amines) and subsequent release of short-lived alkylating intermediates. The mutagenic effect of MNNG can be reduced or enhanced respectively by decreasing or increasing the intracellular thiol levels. As demonstrated with MNU, intracellular thiol concentrations (in milli/molar range), which is high enough to bring about the activation of MNNG, are not sufficiently high to protect DNA from damage by the alkylating intermediate. Extracellular levels of thiols 'protect' the cells simply by increasing the decomposition of MNNG in the treatment solution.
Carcinogenesis 1987 Oct
PMID:Mechanism of N-acetylcysteine (NAC) and other thiols as both positive and negative modifiers of MNNG-induced mutagenicity in V79 Chinese hamster cells. 365 88

4,5-Epoxy-4,5-dihydro-1-nitropyrene (1-nitropyrene 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-nitropyrene 9,10-oxide), which are electrophilic metabolites formed during the metabolism of the environmental pollutant, 1-nitropyrene, reacted slowly with glutathione. The rate of conjugation was greatly enhanced by the addition of purified rat liver glutathione (GSH) transferases, with transferases 3-3 and 4-4 exhibiting higher catalytic activities than transferases 1-1, 2-2 and 7-7. Two GSH conjugates were formed from each of the oxides: 1-nitropyrene 4,5-oxide gave a 1:1 mixture of 4-(glutathion-S-yl)-5-hydroxy-4,5-dihydro-1-nitropyrene and 5-(glutathion-S-yl)-4-hydroxy-4,5-dihydro-1-nitropyrene while 1-nitropyrene 9,10-oxide gave a 2:1 mixture of 9-(glutathion-S-yl)-10-hydroxy-9,10-dihydro-1-nitropyrene and 10-(glutathion-S-yl)-9-hydroxy-9,10-dihydro-1-nitropyrene. Both K-region oxides were converted to trans-dihydrodiols by hepatic microsomal epoxide hydrase, and faster rates were observed with 1-nitropyrene 4,5-oxide. In subsequent experiments [4,5,9,10-3H]1-nitropyrene was administered to Sprague-Dawley rats by intravenous and intraperitoneal injections. HPLC analysis of biliary metabolites indicated the presence of four GSH conjugates that were identical to those obtained from reactions of the K-region oxides with GSH. In addition, glucuronide conjugates were detected from trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene (1-nitropyrene trans-4,5-dihydrodiol) but not trans-9,10-dihydroxy-9,10-dihydro-1-nitropyrene (1-nitropyrene trans-9,10-dihydrodiol). These data combined with earlier studies indicate that 1-nitropyrene is oxidized preferentially to 1-nitropyrene 4,5-oxide and that, while the main detoxification pathway of 1-nitropyrene 9,10-oxide is GSH conjugation, 1-nitropyrene 4,5-oxide is excreted via both GSH conjugation and dihydrodiol formation followed by O-glucuronidation.
Carcinogenesis 1987 Dec
PMID:In vivo and in vitro formation of glutathione conjugates from the K-region epoxides of 1-nitropyrene. 367 4

Selenium (Se) compounds have shown an inhibitory effect on chemically induced tumours in several laboratory models and there is an inverse epidemiological relationship between Se status and certain types of cancer. Little is known about the influence of Se on the development of stomach cancer. Three different forms of dietary Se, selenomethionine, sodium selenite, and high-selenium yeast were investigated as possible inhibitors of benzo(a)pyrene-induced forestomach tumours in mice. The effects of sodium selenite in combination with vitamin E, and of Se-deficiency were also studied. None of the dietary modifications had any effect on tumour incidence or number. Marked elevations of whole-blood glutathione peroxidase (GSH-Px) activities were observed in animals supplemented with all Se-compounds. High-selenium yeast caused the largest increase of GSH-Px activity followed by sodium selenite and selenomethionine. The results indicate that the inhibitory effect of Se on carcinogenesis may be specific with respect to organ site or tumour cell examined.
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PMID:Effects of dietary selenium compounds on benzo (a)-pyrene-induced forestomach tumours and whole-blood glutathione peroxidase activities in C3H mice. 375 57

Biological thiols are known to play an important role in the detoxification of xenobiotics, including chemical carcinogens. To determine the influence of cellular thiols on carcinogen induction of hepatic DNA damage in the rat, diethylmaleate (DEM) administration was used to deplete intracellular glutathione (GSH). The effects of administration of the synthetic thiols, N-acetylcysteine (NAC) and alpha-mercaptopropionylglycine (alpha MPG), on the induction of DNA lesions were also examined. Pretreatment with DEM reduced liver GSH levels by greater than 70%. As assessed by the technique of alkaline elution, subsequent administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) resulted in DNA damage 4 h post MNNG treatment which was 4- to 8-fold greater than that induced in the livers of rats treated with MNNG alone. However, DEM pretreatment had little effect on the extent of DNA damage induced by methylnitrosourea (MNU). DEM alone did not cause any measurable DNA damage. Pretreatment with alpha MPG or NAC reduced MNNG-induced DNA damage by as much as 77%. In contrast, MNU-induced DNA damage was increased by alpha MPG treatment whereas NAC treatment was without effect. These results indicated that in the rat liver, the activity of some DNA alkylating agents may be modulated in varying degree by the concentration of intracellular thiols. These data support the notion that thiols play an important role in protection against carcinogen damage, and that synthetic thiols such as alpha MPG and NAC may be useful as anti-carcinogenic agents against certain carcinogens.
Carcinogenesis 1986 Oct
PMID:Protective role of thiols in carcinogen-induced DNA damage in rat liver. 375 65


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