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)

The alpha, mu and pi classes of glutathione S-transferase (GST) were evaluated as early immunocytochemical markers for the development of atypical foci within the pancreases of azaserine treated rats. Changes detected with haematoxylin and eosin (H&E) were compared with those detected by immunocytochemistry using antibodies raised against each class of GST. All foci detected with H&E staining were classified as acidophilic atypical acinar cell nodules (AACN), which have previously been reported in this model. All of these AACN overexpressed GST mu. However, 64% of foci detected with GST mu staining had not been identified as AACN during a prior examination with H&E. Re-evaluation of the H&E sections revealed that some of these foci showed subtle morphological changes which are indicative of AACN. In many cases, however, no morphological difference could be seen with H&E staining. We conclude that immunocytochemical staining for GST mu is a more reliable and sensitive method than H&E for detecting the early stages of azaserine-induced foci. Furthermore, we suggest that studies on the incidence and growth of these foci can be shortened considerably if GST mu staining is used in conjunction with H&E.
Carcinogenesis 1991 Jul
PMID:Glutathione S-transferase (mu class) as an early marker of azaserine-induced foci in the rat pancreas. 171 77

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
Carcinogenesis 1991 Jul
PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

To develop analogues of phenylalkyl isothiocyanate with less toxicity and better biological activity, two water-soluble phenylalkyl isothiocyanate-cysteine conjugates, S-[N-benzyl(thiocarbamoyl)]-L-cysteine (1) and S-[N-(3-phenylpropyl)(thiocarbamoyl)]-L-cysteine (2), were synthesized. The induction of increased activity of the detoxifying enzyme glutathione S-transferase by the conjugates and their parent compounds was determined and compared in several tissues of A/J mice. The biological evaluation revealed that the conjugates as GST enzyme inducers appeared to be less toxic and even more potent than the parent compounds in the mouse bladder. Compounds 1 was much more active than 2 in all the tissues examined, while their parent compounds showed an inverse order of activity. Thus, an increase in the alkyl chain length of the parent isothiocyanates or a decrease in the alkyl length of the conjugates could result in higher enzyme-inducing activity in the same compound series. Since a number of nitrosamines have been identified as prime bladder carcinogens and phenylalkyl isothiocyanates have been reported to inhibit a wide range of carcinogenic nitrosamines, the corresponding conjugates may serve as prodrugs to protect against nitrosamine-induced urinary bladder carcinogenesis once they are delivered to the target organ.
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PMID:Phenylalkyl isothiocyanate-cysteine conjugates as glutathione S-transferase stimulating agents. 173 27

Reduced expression of the mu-isozyme of glutathione S-transferase (GST; EC 2.5.1.18) has been associated with increased lung cancer risk. We studied the association between GST-mu expression and DNA damage as measured by sister chromatid exchanges (SCE) in healthy male smokers. SCE levels were higher in the 71 GST-mu-deficient smokers compared to the 83 non-deficient smokers (5.24 versus 4.97 SCE/lymphocyte; P = 0.09). In smokers having high plasma cotinine levels (greater than median of 315 ng/ml), this mu-related difference was more pronounced (5.50 versus 4.97; P = 0.01), whereas it was absent in smokers having low cotinine levels (4.95 versus 4.97; P = 0.92). Increased cytogenetic damage in GST-mu-deficient heavy smokers may thus explain the association between GST-mu expression and lung cancer.
Carcinogenesis 1992 Feb
PMID:Increased cytogenetic damage in smokers deficient in glutathione S-transferase isozyme mu. 174 22

We have previously shown that 2-hydroxamino-1-methyl-6-phenylimidazo[4,5-b]pyridine(2-h ydroxamino-PhIP) is the principal metabolite leading to mutations in Salmonella typhimurium TA98 and DNA damage in mammalian cells. In rat hepatocytes this metabolite can be further conjugated to 2-(N-beta-D-glucuronopyranosyl (hydroxamino)-1-methyl-6-phenylimidazo[4, 5-b]pyridine[N(OH)-gluc-PhIP]. Its rate of formation was increased in hepatocytes from polychlorinated biphenyl (PCB)-pretreated animals. This metabolite is the main metabolite of PhIP in bile and it is hydrolyzed both by human and rat intestinal bacteria. Smaller amounts are excreted into urine. The evidence for the proposed structure is based on 1H- and 13C-NMR, beta-glucuronidase-lability giving 2-hydroxamino-PhIP upon hydrolysis and on the results obtained by using biochemical enzyme inhibitors. N(OH)-gluc-PhIP may be important for genotoxic lesions and tumors of 2-amino-1methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in extrahepatic tissue. In hepatocytes and bile from PCB-pretreated rats a PhIP-glutathione conjugate, 2-glutathionyl-1-methyl-6-phenylimidazo[4,5-b]pyridine (GSH-PhIP) was also found. The evidence for the proposed structure is based on 1H-NMR and high-resolution mass spectrometry. The metabolite can also be produced by a direct nucleophilic substitution of the nitro group in 2-nitro-PhIP by glutathione (GSH) in vitro. The metabolite did not form from 2-hydroxamino-PhIP and GSH either directly or in the presence of glutathione S-transferase. The formation of GSH-PhIP in rat liver and isolated cells only at a high rate of 2-hydroxamino-PhIP formation (PCB-treated animals) indicates that 2-nitro-PhIP may be formed in the liver during such N-oxidation of PhIP.
Carcinogenesis 1991 Dec
PMID:Formation of a glutathione conjugate and a semistable transportable glucuronide conjugate of N2-oxidized species of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat liver. 174 23

Analysis of the heterogeneity of glutathione S-transferase (GST) isozyme expression was carried out by immunohistochemical evaluation of human colon biopsy tissue from 30 patients. Using polyclonal antibodies specific for the GST alpha, mu and pi families of isozymes, an increased expression of pi was found in 21/30 carcinoma specimens compared to their pair-matched controls. This isozyme was the most prevalent in all colon samples. GST mu was expressed at reduced levels in 20/30 carcinoma specimens when compared to normal. GST alpha showed no consistent change. Analysis of the immunostaining in different cell types showed that the highest intensity stain for all isozymes was in the columnar epithelial cells. These cells were primarily responsible for the proportional changes in GST pi and mu between carcinoma and normal tissues. In addition, goblet (crypt), endothelial and muscle cells stained positively. In the lamina propria, lymphocytes and phagocytes stained positively, while fibroblasts, plasma cells and leukocytes were negative. Endocrine cells were also negative. The differential expression of GST pi and mu, confirming biochemical data, supports the potential utility of GST pi as a carcinoma marker.
Carcinogenesis 1991 Dec
PMID:Immunohistochemical localization of glutathione S-transferases alpha, mu, and pi in normal tissue and carcinomas from human colon. 174 43

Potential synergism among 5 heterocyclic amines at low doses in the induction of glutathione S-transferase placental form (GST-P)-positive liver cell foci was examined in an 8-week experiment using male rats initially given diethylnitrosamine (200 mg/kg, ip). The heterocyclic amines applied were 3-amino-1-methyl-5H-pyrido[4,3-b]indole (500 ppm), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (500 ppm), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (800 ppm), 2-amino-9H-pyrido[2,3-b]indole (800 ppm), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 400 ppm). Separate groups received each chemical at the dose used in earlier carcinogenicity assays (above doses), at 1/5 or 1/25 of these, or all 5 chemicals together, each at the 1/5 or 1/25 levels. The numbers and areas of GST-P-positive foci were significantly increased with all chemicals, except for PhIP, at the highest dose, the results being consistent with the reported liver carcinogenicity. In the combined treatment at the 1/5 dose levels, synergistic enhancement occurred; the numbers and areas of foci were significantly increased above the sums of individual data. However, this was not the case for the 1/25 dose groups. Although the synergism between pyrolysis products in liver carcinogenesis depended on the dose and combination of chemicals, the findings, together with those from a previous experiment using 5 different heterocyclic amines, are of particular significance since several heterocyclic amines might be simultaneously generated during cooking of foodstuffs.
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PMID:Synergistic enhancement of glutathione S-transferase placental form-positive hepatic foci development in diethylnitrosamine-treated rats by combined administration of five heterocyclic amines at low doses. 177 61

Polychlorinated biphenyls (PCBs) are a group of industrial chemicals that are widely distributed in the environment. Because these compounds occur as mixtures, studies of their possible interactive effects are essential for an understanding of the mechanism of the toxicity of these mixtures. For the determination of a possible interaction of the effects in vivo of 2,5,2',5'-tetrachlorobiphenyl (TCB) and 3,4,3',4'-TCB, rats were exposed to a single dose of diethylnitrosamine (DEN) and subsequently to 0.1 p.p.m. 3,4,3',4'-TCB and/or 10 p.p.m. 2,5,2',5'-TCB in the feed for 1 year. The two major targets of PCB toxicity, the liver and the peripheral blood, were examined after these treatments. TCB treatment after DEN exposure caused a predominance of increased placental glutathione S-transferase (PGST) and deficiencies of ATPase as preneoplastic markers in focal hepatic lesions. When 0.05% phenobarbital (PB) was administered after DEN exposure, the distribution of markers in altered hepatic foci (AHF) was essentially equal for increased PGST and gamma-glutamyltranspeptidase (GGT) and for ATPase deficiency. Many of these AHF also exhibited increased P450 b/e expression. Our results demonstrated that the two PCB congeners interacted in vivo to produce an increase in AHF that were PGST positive and ATPase negative. PGST-positive and ATPase-negative AHF correlated best with focal areas of P450 b/e expression. The combination of the two PCBs caused a greater than additive decrease in the total number of lymphocytes and antibody-producing B-cells. Also the thymocyte-dependent T-helper cells isolated from the animals receiving the combination of TCBs demonstrated a morphologically abnormal subpopulation. The results indicate that the interaction of 2,5,2',5'-TCB and 3,4,3',4'-TCB in vivo induced much greater toxicity and mutagenicity in peripheral lymphocytes and hepatocytes than treatment with either congener alone.
Carcinogenesis 1991 May
PMID:Study of the separate and combined effects of the non-planar 2,5,2',5'- and the planar 3,4,3',4'-tetrachlorobiphenyl in liver and lymphocytes in vivo. 182 16

Cancer development is a long-term multistep process which allows interventional measure before the clinical disease emerges. The detection of natural substances which can block the process of carcinogenesis is as important as the identification of anti-tumoral drugs since they might be used in chemoprevention of cancer in high-risk groups. In vivo rodent models of chemical carcinogenesis have been used to study plant-derived inhibitors of carcinogenesis such as indoles, coumarins, isothiocyanates, flavones, phenols and allyl-sulfides. Since the standard in vivo rodent bioassay is prolonged and expensive, shorter reliable protocols are needed. Two in vivo medium-term protocols for evaluation of modifiers of carcinogenesis are presented, one related to liver and the other to bladder cancer. Both protocols use rats, last 8 and 36 weeks and are based on the two-step concept of carcinogenesis: initiation and promotion. The protocols use respectively the development of altered foci of hepatocytes expressing immunohistochemically the placental form of glutathione S-transferase and the appearance of pre-neoplastic urothelium and papillomas as the "end-points". The use of these protocols for detection of plant-derived inhibitors of carcinogenesis appear warranted.
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PMID:Medium-term protocols for in vivo evaluation of chemical modifiers of carcinogenesis. 184 12

The present studies were undertaken to elucidate the mechanism(s) of the anti-neoplastic effect of diallyl sulfide (allyl sulfide, DAS), a naturally occurring organosulfide abundant in vegetables of the Allium genus, against benzo[a]pyrene (B[a]P)-induced carcinogenesis in the mouse. DAS treatment caused a significant increase in glutathione S-transferase (GST) activity, an enzyme system responsible for detoxification of a variety of electrophilic xenobiotics including several harmful B[a]P metabolites, of mouse stomach in a dose-dependent manner. This activity in the stomach of mice treated with 25, 50 and 75 mumol DAS was higher by 1.13-, 1.20- and 1.58-fold, respectively, when compared to the control. Purification and quantitation of GST from equal amounts (1.2 g) of control and 50 mumol DAS-treated mice stomach tissues demonstrated that elevation in activity occurred as a result of increased de novo synthesis of the enzyme protein. DAS treatment also resulted in increased pulmonary GST activity, but not in a dose-dependent fashion. On the other hand, treatment of mice with DAS did not alter hepatic GST activity. Interestingly, a small but statistically significant (P less than or equal to 0.05) reduction in kidney GST activity was observed in mice treated with 50 or 75 mumol DAS, as compared to the control. The effect of DAS treatment was also assessed on glutathione (GSH) peroxidase activity, another GSH-dependent detoxification enzyme, in mouse tissues. Treatment of animals with 25, 50 and 75 mumol DAS increased stomach GSH peroxidase activity by 1.64-, 1.93- and 2.52-fold, respectively, over the control. This enzyme activity in the lungs of mice treated with 25, 50 and 75 mumol DAS was higher by 1.44-, 1.54- and 1.21-fold, respectively, when compared to the control. On the other hand, GSH peroxidase activity in liver and kidney was unchanged by DAS treatment. These results suggest that DAS and perhaps other naturally occurring organosulfur compounds may exert an anti-neoplastic effect by modulating GSH-dependent detoxification enzymes.
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PMID:Effect of diallyl sulfide, a naturally occurring anti-carcinogen, on glutathione-dependent detoxification enzymes of female CD-1 mouse tissues. 188 35


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