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

Glutathione (GSH) alone detoxifies electrophiles with an effectiveness which depends on the rate of the reaction and the concentration of GSH. If electrophiles are substrates for GSH transferase isoenzymes, the effectiveness of detoxication is much enhanced due to the increased rate of reaction and it is also independent of GSH concentration to low levels of GSH depletion, since the Km for GSH is approximately 0.1 mM. In this paper detoxication of electrophilic metabolites of the hepatocarcinogen N-methyl-4-aminoazobenzene which are not substrates for GSH transferases and the carcinogenic electrophile derived from the hepatocarcinogen aflatoxin B1 which is a poor substrate is compared with detoxication of electrophiles which are good substrates and which although bacterial mutagens are not carcinogenic in organs containing the appropriate GSH transferases. GSH transferases detoxify not only electrophiles derived from xenobiotics, but also endogenous electrophiles which are usually the consequence of free radical damage in the presence of oxygen to lipids and DNA and include lipid and DNA hydroperoxides and alkenals arising from the decomposition of lipid hydroperoxides. Studies in the rat and other mammals show the GSH transferases to be dimers in which the subunits are members of a gene super-family. There are three, perhaps four multigene families namely, alpha containing subunits 1, 2, 8 and 10; mu containing subunits 3, 4, 6 and 9; pi containing subunit 7 and subunits 5 and 5* which are so far unassigned. Subunit 5* is apparently restricted to the nucleus and is noteworthy for its activity towards DNA hydroperoxides. Studies in the human are not as advanced as in the rat but so far reveal close similarities. The ability of GSH transferases to detoxify electrophiles is important in carcinogenesis at a number of points. They may inhibit initiation and tumour proportion, but they may be advantageous to the developing tumour cell, and may be acquired in increased amounts during malignant progression. In many tumour cells the development of lines resistant to anticancer drugs is associated with an increased expression of GSH transferases, particularly GSH transferase pi in human cells.
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PMID:Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. 305 66

The enzyme-catalysed conjugation of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+/-)-anti-BPDE] with glutathione (GSH) by cytosolic GSH transferases isolated primarily from rat lung has been studied. GSH transferase 4-4 was active in the GSH conjugation of anti-BPDE, whereas transferases 2-2 and 3-3 showed little activity. GSH transferase 1-1 did not contribute to the activity since significant amounts were not detected in the rat lung. Activity was also obtained with several acidic pulmonary GSH transferases and with a newly described form, transferase 7-7, also isolated from rat kidney and from hyperplastic liver nodules. The catalytic efficiency (kcat/Km) of transferase 7-7 was seven times that of transferase 4-4, the most active rat transferase previously identified. When the GSH concentration was varied at constant (+/-)-anti-BPDE concentration in the presence of transferases 4-4, 7-7 or the major acidic transferase, non-linear Lineweaver-Burk plots were obtained. Resolution of the GSH conjugates of the two enantiomers of (+/-)-anti-BPDE by h.p.l.c. showed that all isoenzymes with notable activity were selective (greater than or equal to 97%) for the (+)-enantiomer of anti-BPDE, which is generally considered to be the most carcinogenic form of BPDE. The possibility that one enantiomer inhibits the conjugation of the other enantiomer with GSH cannot be excluded and may quantitatively affect the results obtained.
Carcinogenesis 1986 Feb
PMID:Glutathione transferases in rat lung: the presence of transferase 7-7, highly efficient in the conjugation of glutathione with the carcinogenic (+)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene. 308 Dec 72

The kinetics of the enzymatic conjugation of glutathione (GSH) with the anti-diastereoisomers of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE), trans-3,4-dihydroxy-1,2-epoxy-1,2,3, 4-tetrahydrobenz[a]anthracene (BADE) and trans-1,2- dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (CDE) catalyzed by transferase 4-4 from rat liver have been compared. When the concentration of these diol-epoxides was varied (using 2 mM GSH) the apparent Vmax values were 560, 2100 and 1500 nmol/mg/min for (+/-)-anti-BPDE, (+/-)-anti-BADE and (+/-)-anti-CDE, respectively, with corresponding apparent Km values of 11, 125 and 105 microM. The catalytic efficiency of transferase 4-4 in the GSH conjugation of (+/-)-anti-BADE and (+/-)-anti-CDE is thus approximately one-third of (+/-)-anti-BPDE (0.014 and 0.012 s-1 microM-1 respectively versus 0.042 s-1 microM-1). Similar non-linear Lineweaver-Burk plots were obtained with each diol-epoxide when the concentration of GSH was varied, and two apparent Km values of 0.02-0.04 and 0.4-0.9 mM GSH were estimated. The GSH-conjugates formed with the individual enantiomers of the racemic substrates used were resolved by h.p.l.c. The data indicate that with each diol-epoxide transferase 4-4 is highly selective (greater than or equal to 95%) towards the biologically most active (+)-enantiomer.
Carcinogenesis 1986 Oct
PMID:The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo[a]pyrene, benz[a]anthracene and chrysene. 309 9

Rat and hamster liver cytosolic glutathione (GSH) S-transferases purified by GSH-affinity chromatography have been examined for their effects on the microsome mediated binding of aflatoxin B1 (AFB1) to DNA and on the conjugation of AFB1-2,3-epoxide with GSH. Like previous studies with cytosolic preparations (Raj et al. (1984) Carcinogenesis 5, 879), our present study with purified GSH S-transferases showed 2-3-fold more inhibitory activity of AFB1-DNA binding with hamster than that with the rat. Concomitant with the inhibition of AFB1-DNA binding, increase in AFB1-GSH conjugation occurred. Subunit compositions of GSH S-transferases indicate preponderance of Yb and Ya subunits in the hamster and rat, respectively. The role of GSH S-transferases in modulating AFB1-DNA binding and AFB1 induced hepatocarcinogenesis is discussed.
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PMID:Effect of purified rat and hamster hepatic glutathione S-transferases on the microsome mediated binding of aflatoxin B1 to DNA. 309 33

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.
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PMID:Effects of combined treatments with selenium, glutathione, and vitamin E on glutathione peroxidase activity, ornithine decarboxylase induction, and complete and multistage carcinogenesis in mouse skin. 309 11

We have studied the effects of plasma and of cumene hydroperoxide (CUM) on adenosine diphosphate ribosyl transferase (ADPRT) from mononuclear leukocytes (HML) of patients with colonic adenomatous polyps (n = 22), with colonic hyperplastic polyps (n = 5) and with neither type of polyp (controls) (n = 6). ADPRT was measured after incubation of HML with plasma alone (termed the plasma value), and with plasma plus CUM (50 microM) (the activated value); the difference elicited by CUM was termed the induced value. There was no significant difference in values between the control and hyperplastic polyp groups: these were combined for further analysis. The plasma (P = 0.038), activated (P = 0.009) and induced (P = 0.0024) values of the combined group all differed significantly from those of the adenoma group. At low exposures, CUM stimulated both ADPRT and unscheduled DNA synthesis and, at higher exposures, inactivated both. Pretreatment of HML with vitamin E protected against these effects of CUM, while pretreatment with diamide (which depletes GSH) accentuated the effects. This study demonstrates a differential reaction of ADPRT in patients harboring colonic adenomas and suggests that the origin of this difference may lie in cellular responses to oxidative stress.
Carcinogenesis 1988 Mar
PMID:Effects of cumene hydroperoxide on adenosine diphosphate ribosyl transferase in mononuclear leukocytes of patients with adenomatous polyps in the colon. 312 91

Rainbow trout are known to be more susceptible to aflatoxin B1 (AFB1) hepatocarcinogenesis than coho salmon, or trout pre-fed the carcinogenesis inhibitors beta-naphthoflavone (beta NF), Aroclor 1254 or indole-3-carbinol. The study reported here examined the relationship between AFB1-glutathione (GSH) conjugation and AFB1 carcinogenesis in salmon, trout and trout pre-fed the three inhibitors. The AFB1-glutathione (AFB1-SG) conjugate was not detected in salmon bile and was present in trout bile in amounts representing less than 0.2% of the administered dose 24 hr after injection of [3H]AFB1. The major conjugates were glucuronides of aflatoxicol and aflatoxicol M1. In incubations of isolated liver cell fractions, less than 0.5% of the original AFB1 dose was recovered as AFB1-SG in salmon and trout preparations, compared to 25% in mouse-liver cell preparations. The GSH concentration in livers of the control trout was higher than that for coho salmon but lower than that for trout pre-fed beta NF. Liver GSH-transferase activity in control trout livers was much higher than in the control salmon livers, but was only 62% of that found for trout fed beta NF. There was no apparent relationship among the various groups between liver GSH concentrations, liver GSH-transferase activity, or biliary GSH conjugate, and the degree of carcinogenic response of AFB1. Thus current evidence does not indicate a major role for aflatoxin B1 epoxide-GSH detoxification in coho salmon, or rainbow trout fed any of the three anticarcinogens tested. These results in salmonid fish are contrary to those which suggest AFB1-SG conjugation as a major determinant of AFB1 carcinogenesis and its dietary modulation in rodent models.
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PMID:The significance of glutathione conjugation for aflatoxin B1 metabolism in rainbow trout and coho salmon. 313 Feb 99

Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.
Carcinogenesis 1988 Sep
PMID:Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model. 313 44

To better understand the role of free radicals in liver carcinogenesis, endogenous antioxidant defense systems and the susceptibility of membranes to lipid peroxidation were evaluated in early lesions and in malignant tumors induced by the Solt-Farber resistant hepatocyte protocol. These parameters were also measured in the liver surrounding these tumors. In comparison with the normal liver, both nodules and carcinomas show a different biochemical pattern consisting of decreased glutathione peroxidase (GSH peroxidase) and catalase activities plus increased glutathione reductase (GSSG reductase) activity. In contrast, 1 week after the application of the initiation-selection protocol, the liver displays a high level of glutathione (GSH), high GSSG reductase activity, a reduced production of malondialdehyde and no changes in superoxide dismutase and GSH peroxidase activities. These data suggest that the liver is well protected against reactive oxygen species. During the carcinogenic process, the liver parenchyma surrounding the altered foci recovers from most of the modifications induced by the initiation-selection treatment. These results add additional support for the hypothesis that the appearance of early alterations in the liver, after a carcinogenic treatment, might be an adaptive response to a hazardous environment in which selected cell populations are transformed into nodules and/or carcinomas.
Carcinogenesis 1988 Nov
PMID:Analysis of antioxidant defense systems during rat hepatocarcinogenesis. 318 Mar 39

The effects of homocysteine (Hcy) on one non-transformed (Cl 8) and two malignant clones (Cl 16 and Cl T422) of the C3H/10T1/2 mouse embryo fibroblasts, were examined with regard to toxicity, ability to support growth and effects on methionine (Met) metabolism and glutathione level. Homocysteine in its reduced form (Hcy-SH) was toxic to all cell lines, and the LD90 was estimated to be 1.0 X 10(-4) M for Cl 8 and Cl 16 cells measured by plating efficiency, 0.8 X 10(-4) M for Cl 8 and 0.3 X 10(-4) M for Cl 16 when measured by total cell growth. At toxic concentrations, Hcy-SH showed a drastic effect on cell morphology both in the presence and absence of Met. The same effect was demonstrated with L-cysteine. No toxic effect was seen with homocystine (Hcy-SS-Hcy) or homocysteine thiolactone (Hcy-tl) at similar concentrations. Hcy-tl supported growth of both the non-transformed and malignant cells in Met-deficient medium but with decreasing efficiency in the order Cl 8, Cl 16 and Cl T422. The growth rate constant compared to that of Met-supplemented medium was 0.62 for Cl 8, 0.44 for Cl 16 and 0.38 for Cl T422 cells. The intracellular level of S-adenosylhomocysteine (AdoHcy) increased in all three cell lines in Hcy-tl-supplemented medium. The S-adenosylmethionine (AdoMet) content increased in Cl 8 cells, was constant in Cl 16 cells and decreased in Cl T422 cells under the same conditions. This resulted in a constant ratio of AdoMet/AdoHcy in the non-transformed cells (Cl 8) whereas this ratio decreased by 40% in Cl 16 and by 72% in Cl T422 cells when Hcy-tl replaced Met in the medium. The ability of Hcy-tl to support growth thus seemed to correlate well with alteration in Met metabolism in this cell culture system. The intracellular level of glutathione (GSH) was measured during exponential growth, but showed small variations between non-transformed cells and Cl 16 cells. However, Cl T422 cells showed a distinct lower level of GSH in Met-supplemented medium, and this increased 3- to 4-fold when Met was replaced with Hcy-tl.
Carcinogenesis 1988 Jan
PMID:Growth support and toxicity of homocysteine and its effects on methionine metabolism in non-transformed and chemically transformed C3H/10T1/2 cells. 333 51


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