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)

Induced 10T1/2 cell microsomes were independently reconstituted with [3H]benzo[a]pyrene (BP) and glutathione (GSH) or purified GSH-transferases. Levels of the primary BP anti 7,8-dihydrodiol 9,10-epoxide (r-7,t-8 dihydroxy-t-9,10-oxy-7,8,9,10 tetrahydrobenzo[a]pyrene) hydrolysis product, 7,10/8,9-tetrol, were measured in incubation extracts, enabling us to monitor the level of free anti diol-epoxide in incubations and to determine the independent effects of GSH or GSH-transferases upon it. GSH alone had no effect on anti diol-epoxide levels over the concentration range tested (0-4.0 mM), however, the addition of purified GSH-transferase from rat liver resulted in a dose-dependent conjugation of anti diol-epoxide as well as 9,10-epoxide and 7,8-epoxide with 50% conjugation occurring at 0.036, 0.039 and 0.17 units GSH-transferase/ml, respectively. Free anti diol-epoxide was reduced by greater than 95% when we reconstituted with the GSH-transferase concentration which we measured in 10T1/2 cells (0.15-0.27 units/ml cell cytosol); this GSH-transferase concentration represents only 6% of that found in rat liver. The results suggest that in both 10T1/2 cells and rat hepatocytes GSH-transferase catalyzed GSH conjugation is quantitatively significant in determining the intracellular level of anti diol-epoxide.
Carcinogenesis 1984 Feb
PMID:Quantitative significance of glutathione and glutathione-S-transferase in regulating benzo[a]pyrene anti diol-epoxide level in reconstituted C3H/10T1/2 cell lysates, and comparison to rat liver. 632 Oct 48

The roles of non-enzymatic and enzymatic glutathione (GSH) conjugation in the activation and detoxication of 3-hydroxy-amino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) were studied in vitro. N-OH-Trp-P-2 is an active metabolite of 3-amino-1-methyl-5H-pyrido[4,3-d]indole (Trp-P-2), a mutagenic and carcinogenic heterocyclic amine. 3-Nitroso-1-methyl-5H-pyrido[4,3-b]indole (NO-Trp-P-2) reacted rapidly and non-enzymatically with GSH to form N-OH-Trp-P-2 and a small amount of two GSH conjugates (CN-1 and CN-2). On the other hand, non-enzymatic reaction of GSH with N-OH-Trp-P-2 was very slow, but the GSH conjugation with N-OH-Trp-P-2 was catalyzed by rat liver GSH transferase and a rat liver cytosol fraction to form three conjugates (CH-1, CH-2 and CH-3). The enzymatic conjugation was effectively inhibited by organic tin compounds which are known as powerful GSH transferase inhibitors. The conjugates were unstable enough to yield Trp-P-2 (from CN-1, CN-2 and CH-2) or N-OH-Trp-P-2 (from CH-3) on incubation at 37 degrees C for 30-60 min. Only CH-1 was stable under similar conditions. The mutagenicities of the GSH conjugates and the effects of GSH and GSH transferase were studied by using Salmonella typhimurium TA98 as the tester strain. The GSH conjugates except for CH-3 were completely detoxicated products, but CH-3 was found to be a more potent mutagen than N-OH-Trp-P-2. The mutagenicity of CH-3 seemed to be due to the direct action of the conjugate, and not to N-OH-Trp-P-2 formed from it.
Carcinogenesis 1983 Dec
PMID:Activation and detoxication of N-hydroxy-Trp-P-2 by glutathione and glutathione transferases. 636 Apr 5

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

The formation of an aflatoxin B1-reduced glutathione (AFB1-GSH) conjugate in in vitro systems has been examined. AFB1 was activated by a chicken liver microsomal system and factors affecting the subsequent conversion to the AFB1-dihydrodiol or conjugation with GSH were investigated by HPLC. A requirement for glutathione S-transferase in the formation of the AFB1-GSH conjugate was observed. Studies using CM-cellulose columns showed the fractions containing glutathione S-transferase B activity were the most effective in catalysing the formation of the AFB1-GSH conjugate. The possibility of changes in the level of AFB1-GSH conjugate production in the liver during carcinogenesis by AFB1 has been examined. It has been found, using freshly isolated rat hepatocytes, that low level feeding with AFB1 in vivo increases the production of the conjugate in vitro. Further increases in the production of the conjugate by hepatocytes in vitro, accompanying increases in the preneoplastic lesions, are achieved by partially hepatectomising the AFB1-fed animals. Partial hepatectomy of control-fed animals yielded no similar changes. The AFB1/partial hepatectomy treatment resulted in increased levels of all the glutathione S-transferase activities fractionated on CM-cellulose. Macromolecular binding of AFB1 and/or of its metabolites was detected in the fractions containing glutathione S-transferase activity, but there was no evidence for a greater binding in the glutathione S-transferase B/ligandin containing fractions. Furthermore fractionation on Sephadex G-75 indicated a predominance of binding of AFB1 to proteins of a higher molecular weight than the glutathione S-transferases, although some binding in the molecular weight range of the latter was observed.
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PMID:The requirement for glutathione S-transferase in the conjugation of activated aflatoxin B1 during aflatoxin hepatocarcinogenesis in the rat. 641 67

The effect of dietary selenium levels on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors was examined in mice fed a semi-purified diet (20% casein, 50% sucrose, 5% corn oil). (C57BLxDBA/2f)F1 (BD2F1) female mice were fed diets containing 0.2, 0.5, 1.0 and 2.0 p.p.m. selenium starting at 7 weeks of age. The mammary tumor incidence was 56, 30, 25 and 16%, respectively, after the mice were on the diet for 9 months. In a second experiment, BALB/cV female mice were fed diets containing 0.2 and 2.0 p.p.m. selenium. After 9 months on the diet, the mammary tumor incidence was 39 and 7%, respectively. Both strains of mice grew equally well on the 0.2 and 2.0 p.p.m. selenium diets indicating that the highest dietary selenium level was compatible with normal growth. The selenium concentration and selenium dependent-glutathione peroxidase (GSH-Px) activity of mammary glands from control BD2F1 mice fed 0.2, 1.0 and 2.0 p.p.m. dietary selenium was examined at 8, 9 and 10 months of age. As in previous experiments in adult BALB/c mice, the concentration of mammary gland selenium, but not GSH-Px activity, increased with increasing levels of dietary selenium. These results document that nutritional levels of dietary selenium (0.5 p.p.m. Se) as well as non-toxic higher levels (2.0 p.p.m. Se) inhibit DMBA-induced mammary tumorigenesis.
Carcinogenesis 1983 Sep
PMID:Effect of dietary selenium levels on 7,12-dimethylbenzanthracene-induced mouse mammary tumorigenesis. 641 77

A vitamin A (retinyl acetate)-deficient diet enhanced liver cancer in rats exposed to aflatoxin B1 (AFB1) and also caused a 29% incidence of colon cancer. The following factors were considered in attempts to define conditions under which vitamin-A-deprived rats were more susceptible to colon cancer induced by AFB1: liver morphology, enterohepatic recirculation, level of reduced glutathione (GSH) in liver, and differing capacities for conjugation of aflatoxin to GSH. Enzyme concentrations in liver, in intestinal and colon mucosa, and in intestinal and colon contents suggested that AFB1 may have different metabolites and that there may be differing susceptibilities of colon mucosa to carcinogenesis. Binding studies supported this hypothesis. Previous studies have shown that colon epithelium from vitamin-A-deficient rats binds more AFB1 than colon epithelium from normal, vitamin-A-supplemented animals. In the present study, vitamin A supplementation to the vitamin-A-deficient rats before oral administration of 3H-AFB1 significantly decreased the binding capacity at 12 and 15 hours after dosing with the carcinogen. These results suggest that the effect of vitamin A on the metabolism of the carcinogen, particularly on binding of AFB1 to cellular macromolecules, may be the mechanism by which vitamin A modifies aflatoxin's carcinogenic potential, influenced in part through enzymatic mechanisms.
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PMID:Vitamin A and aflatoxin: effect on liver and colon cancer. 641 17

The prostaglandin synthase and horseradish peroxidase catalyzed binding of p-phenetidine to DNA was investigated. The addition of arachidonic acid to an incubation containing ram seminal vesicle microsomes, [14C]p-phenetidine and DNA resulted in a rapid incorporation of radioactivity into DNA. This was inhibited by greater than 75% by indomethacin (0.1 mM) or butylated hydroxyanisole (0.5 mM). Hydrogen peroxide was as efficient as arachidonic acid in mediating the activation of p-phenetidine thus implicating the involvement of the hydroperoxidase activity of prostaglandin synthase in this reaction. Horseradish peroxidase and hydrogen peroxide also catalyzed the activation of p-phenetidine to DNA-binding metabolites. Reduced glutathione (GSH) stimulated the binding of p-phenetidine to DNA by greater than 3-fold in both the prostaglandin synthase and the horseradish peroxidase system, whereas cysteine and N-acetylcysteine reduced the DNA-binding in the prostaglandin synthase system by up to 62% under the conditions used. Furthermore, water-soluble metabolites formed in the presence of GSH also bound to DNA. Seventy-two hour dialysis of DNA samples from incubations with GSH present reduced the amount of bound material by 75%. In contrast, the radioactivity which associated with DNA in the absence of GSH was not decreased by dialysis.
Carcinogenesis 1984 Feb
PMID:Prostaglandin synthase and horseradish peroxidase catalyzed DNA-binding of p-phenetidine. 642 1

Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and the anti-isomer of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) were found to be activated by microsomes isolated from 3-methylcholanthrene (MC)-treated rats to reactive intermediates that bound covalently to microsomal proteins. The extent of binding was markedly reduced by the presence of reduced glutathione (GSH) or cysteine. Fluorescence spectroscopic studies on the products derived from BP-7,8-diol and BPDE after microsomal activation in presence of GSH or cysteine revealed the formation of a common reactive intermediate with unique fluorescence properties. The involvement of cytochrome P-448 in the activation of BP-7,8-diol and BPDE to protein-binding products was inferred by the requirement for NADPH and almost complete inhibition by alpha-naphthoflavone. Furthermore, microsomes from MC-treated rats could be replaced by a reconstituted system containing purified cytochrome P-448, NADPH-cytochrome reductase and co-factors. The conjugation of the reactive intermediates from BP-7,8-diol and BPDE with GSH or cysteine did not require the presence of either microsomes or cytosol, thus indicating a non-catalytic reaction. These results emphasize the importance of cellular nucleophiles such as GSH and cysteine in the deactivation of reactive benzo[a]pyrene (BP) intermediates and also provides evidence for the further activation of the ultimate carcinogen BPDE to more reactive electrophiles and may thus have relevance concerning the regulation of BP-induced carcinogenesis.
Carcinogenesis 1984 Feb
PMID:Metabolic activation of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and the inhibitory effect of glutathione and cysteine. 642 2

Microsome mediated aflatoxin B1 (AFB1) binding to exogenous and endogenous DNA and its modulation by cytosolic glutathione (GSH) S-transferases have been examined in rat and hamster livers. Kinetic studies over a wide range of cytosol concentrations indicate that cytosol from the hamster is several-fold more effective than that from the rat in inhibiting AFB1 binding to exogenous calf thymus DNA mediated by microsomes from either species. Low concentrations of GSH (0.1-0.2 mM) are required for 50% inhibition of AFB1-DNA binding by cytosol. With exogenous DNA, combined microsome-cytosol fractions from the hamster give more AFB1-DNA binding than those from the rat. However, with nuclei as a source of endogenous DNA, AFB1-DNA binding is less with combined microsome-cytosol fractions from the hamster than those from the rat. Cytosolic inhibition of AFB1-DNA binding is almost completely reversed in the presence of 1 mM levels of either trichloropropene oxide or styrene oxide. Quantitation of AFB1-DNA binding and AFB1-GSH conjugation indicate an inverse relationship between these two processes. Cytosol from the rat has less capacity than that from the hamster to form an AFB1-GSH conjugate. Hepatic GSH levels are about equal (6-7 mM) in both species. I.p. administration of [14C]AFB1 2 h before sacrifice gives more AFB1 binding to hepatic nuclear DNA in rats than in hamsters. However, depletion of hepatic GSH levels by 80% by i.p. administration of diethylmaleate (600 mg/kg) increases AFB1-DNA binding 2- to 3-fold in both species. The role of cytosolic GSH S-transferases in modulating hepatic AFB1-DNA binding in rats and hamsters is discussed.
Carcinogenesis 1984 Feb
PMID:Modulation of microsome-mediated aflatoxin B1 binding to exogenous and endogenous DNA by cytosolic glutathione S-transferases in rat and hamster livers. 642 4

Dietary administration of 2(3)-tert-butyl-4-hydroxyanisole (BHA) to mice caused an increase in the hepatic soluble glutathione S-transferase activity towards (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) of approximately 5-fold whereas that towards 1-chloro-2,4-dinitrobenzene (CDNB) was increased by approximately 14-fold. Whereas with either substrate the catalytic capacity of the enzyme was elevated by BHA treatment, there was little effect on the Km for CDNB but an increase in the Km for BPDE as substrates. The results thus suggest that BHA-induced GSH S-transferase activity may be of limited importance for protection from certain reactive intermediates of polycyclic aromatic hydrocarbons.
Carcinogenesis 1984 Jun
PMID:Induction of hepatic glutathione S-transferase activity by butylated hydroxyanisole and conjugation of benzo[a]pyrene diol-epoxide. 642 16


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