Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modulatory effects observed due to clove administration (0.5%, 1% and 2% w/w in the diet) to Swiss albino mice for 10, 20 and 30 days in the hepatic levels of cytochrome P-450 (Cyt. P-450), cytochrome b5 (Cyt. b5), aryl hydrocarbon hydroxylase (AHH), glutathione S-transferase (GST), DT-diaphorase (DTD), acid soluble sulfhydryl (SH) content and radiation-induced malondialdehyde (MDA) formation were recorded. Enhanced GST, Cyt. b5 and SH levels were observed in all the treatment groups, excepting those maintained on a 0.5% diet for 10 days which did not show significant increase in the GST and SH levels as compared to their respective controls. Significant reduction in Cyt. P-450 and MDA levels was observed in all groups at 30 days duration. While AHH levels remained unaltered by clove administration, DTD activity was elevated by 1% and 2% clove diets at 30 days duration. An in vivo bone marrow micronucleus assay demonstrated that administration of 0.5% and 2% clove diets for 10 days neither significantly induced micronuclei nor could effectively modulate the 7, 12-dimethylbenz[a]anthracene genotoxicity in mice. The results suggest whole cloves as potential chemopreventive agents.
Cancer Lett 1991 Oct
PMID:Modulatory influences of clove (Caryophyllus aromaticus, L) on hepatic detoxification systems and bone marrow genotoxicity in male Swiss albino mice. 191 28

The effects of all-trans-retinoic acid (RA) on hepato-carcinogenesis induced by N-nitrosomorpholine (NNM) and on the expression of myc p110 proteins were investigated in male Sprague-Dawley rats. Rats received i.m. injections of RA twice a week and, from the beginning of the experiment, were given drinking water containing NNM for 8 weeks. Pre-neoplastic and neoplastic lesions staining positively for gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase placental type (GST-P) or myc p110 protein were examined histochemically. At week 18, quantitative histological analysis showed that prolonged administration of RA resulted in a significant reduction in the number, size and volume of GGT-positive and GST-P-positive hepatic lesions. Administration of RA also caused a significant increase in the proportion of myc p110-negative lesions to the total pre-neoplastic lesions observed. Myc p110-negative lesions had a significantly lower mitotic index than myc p110-positive lesions. These findings indicate that RA inhibits hepatocarcinogenesis and suggest that this effect may be related to its influence in reducing the expression of myc gene proteins and its subsequent inhibition of cell proliferation in pre-neoplastic lesions.
Int J Cancer 1991 Sep 30
PMID:Inhibition by retinoic acid of hepatocarcinogenesis induced by N-nitrosomorpholine and of expression of myc oncogene protein in Sprague-Dawley rats. 191 45

Individual variations in activity of pulmonary enzymes that metabolize tobacco-derived carcinogens may affect an individual's cancer risk from cigarette smoking. To investigate whether some of these enzymes (e.g., cytochrome P450IA-related) can serve as markers for carcinogen-induced DNA damage accumulating in the lungs of smokers, non-tumorous lung tissue specimens were taken during surgery from middle-aged men with either lung cancer (n = 54) or non-neoplastic lung disease (n = 20). Phase I (AHH, ECDE) and phase II (EH, UDPGT, GST) enzyme activities, glutathione and malondialdehyde contents were determined in lung parenchyma and/or bronchial tissues; some samples were analyzed for DNA adducts, using 32P-postlabeling. Data analysis of subsets or the whole group of patients yielded the following results. (1) Phase I and II drug-metabolizing enzyme (AHH, EH, UDPGT, GST) activities in histologically normal surgical specimens of lung parenchyma were correlated with the respective enzyme activities in bronchial tissues of the same subject. (2) In lung parenchyma, enzyme (AHH, ECDE, EH, UDPGT) activities were significantly and positively related to each other, implying a similar regulatory control of their expression. (3) Mean activities of pulmonary enzymes (AHH, ECDE) were significantly (2- and 7-fold, respectively) higher in lung cancer patients who had smoked within 30 days before surgery (except GST, which was depressed) than in cancer-free subjects with a similar smoking history. (4) In the cancer patients, the time required for AHH, EH and UDPGT activities to return to the level found in non-smoking subjects was several weeks. (5) Bronchial tree and peripheral lung parenchyma preparations exhibited a poor efficiency in activating promutagens to bacterial mutagens in Salmonella. However, they decreased the mutagenicity of several direct-acting mutagens, an effect which was more pronounced in tissue from recent smokers. GSH concentration and GST activity were positively correlated with mutagen inactivation in the same sample. (6) In recent smokers, AHH activity in lung parenchyma was positively correlated with the level of tobacco smoke-derived DNA adducts. (7) Pulmonary AHH and EH activity had prognostic value in tobacco-related lung cancer patients. (8) An enhanced level of pro-oxidant state in the lungs was associated with recent cigarette smoking. Malondialdehyde level in lung parenchyma was associated with the degree of small airway obstruction, suggesting a common free radical-mediated pathway for both lung cancer induction and small airway obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carcinogen metabolism and DNA adducts in human lung tissues as affected by tobacco smoking or metabolic phenotype: a case-control study on lung cancer patients. 194 27

Altered hepatic foci (AHF) were analyzed by quantitative stereology on frozen serial sections stained sequentially for gamma-glutamyltranspeptidase (GGT), canalicular adenosine triphosphate (ATPase), glucose-6-phosphatase (G6Pase), and the placental isoenzyme of glutathione S-transferase (GST). Livers for these analyses were obtained from both male and female rats of different ages which had been subjected to initiation with a nonnecrogenic dose of diethylnitrosamine following a 70% partial hepatectomy with subsequent phenobarbital (PB) feeding. Different combinations of these four marker alterations (from single marker to four-marker combinations) were used to analyze the data, and the results were compared for their ability to detect AHF. In rats on the above protocol, GST was the single most effective marker, exhibiting a high sensitivity for scoring both number and volume of foci. There was a high degree of overlap with GGT. The combination of the four different markers, GST/GGT/ATPase/G6Pase, scored 80% more foci in number and 60% more in volume than the routinely used GGT/ATPase/G6Pase method. When all four markers were used to score AHF, PB promotion was equally effective in both sexes at weaning and at 6 months of age, but at 1 year of age males showed a dramatic reduction in the effectiveness of PB as a promoting agent, both for number and volume percentage of liver occupied by AHF. On the other hand, initiation was more effective in the male at weaning and at 6 months of age, although by the 12-month point no distinction between the sexes could be made. When only GGT was used as a marker, promotion by PB appeared to be markedly less effective in males than in females at all ages. In the absence of PB administration, both the number and volume fraction of AHF in the livers of both males and female increased with age. Likewise, both the number of AHF per liver and their volume fractions increased with age in both sexes when uninitiated animals were fed PB, although only after a 6-month lag in females. These experiments demonstrate that the stages of initiation and promotion in hepatocarcinogenesis in the rat as monitored by the number and volume percentage occupied of AHF are altered by both the age and the sex of the animal. The combination of GGT and GST identified all AHF scored by the GST/GGT/ATPase/G6Pase set of markers and thus may be the most efficient combination of markers of AHF resulting from promotion by PB.
Cancer Res 1990 Feb 01
PMID:Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. 196 47

Female adult rats were as responsive as males to initiation by diethylnitrosamine (DEN) as measured by numbers of GST-P positive hepatocytes appearing early, and do develop hepatocellular cancers. However, when females and males were exposed to four promotion regimens including orotic acid (OA), choline deficiency, deoxycholic acid (DOC), or selection for resistance (to 2-acetylaminofluorene; 2-AAF) after DEN initiation, very significant sex differences were observed with respect to oval cell proliferation and growth rates of hepatocytic foci. These results suggest that responses to promotion such as growth of foci and oval cell proliferation can accompany carcinogenesis but may not be essential to the development of hepatocellular cancer.
Cancer Lett 1990 Apr 20
PMID:Sex differences in response to four promotion regimens in spite of common first cellular steps in the hepatocellular cancer process initiated by diethylnitrosamine. 197 Feb 74

Increased expression of the mdr1 gene, encoding the 175 kDa P-glycoprotein, and the gst-pi gene, encoding the anionic isozyme of glutathione S-transferase (GST), have previously been detected in continuous human breast cancer cell lines selected in vitro for resistance to doxorubicin. In this present study we have measured RNA levels of mdr1 and gst-pi in primary human breast tumour biopsies prior to chemotherapy and from tumours which have different inherent responses to doxorubicin treatment, including colon, head and neck squamous cell carcinomas and myeloid leukaemias. Detectable levels of mdr1 mRNA was observed in 25 out of 49 breast tumours, with up to a 100-fold range in expression. A narrower range of gst-pi expression has also been observed in these tumours. Chemosensitivity of cells grown in short-term culture from some of the breast tumours has been measured by an in vitro colony forming assay in the presence of doxorubicin. Comparison of the dose of doxorubicin causing 50% inhibition of growth (ID50) with RNA levels showed that the tumours with high mdr1 expression had high ID50, while the more sensitive explants had low mdr1 expression. These results support a role for mdr1 gene expression in determining the response of human breast cancer cells to chemotherapy.
Br J Cancer 1990 May
PMID:Expression of mdr1 and gst-pi in human breast tumours: comparison to in vitro chemosensitivity. 197 Sep 34

We have studied the expressions of nine proto-oncogenes (c-myc, N-myc, c-fos, C-jun, p53, H-ras, N-ras, c-raf, hst) and two other genes (PCNA, GST-P) during the spontaneous development of hepatocellular carcinomas (HCCs) in LEC rats. Expression of c-myc, H-ras, N-ras, C-raf, p53 and PCNA genes was detected, but this did not significantly change during the development of HCCs in LEC rats. Expression of N-myc and hst genes was not detectable. Expression of c-fos gene was detected in one HCC case out of four. Significantly increased expression of c-jun gene was observed in the liver tissues of LEC rats aged 8 months. This high expression was decreased with the development of HCCs. On the other hand, the expression of GST-P gene increased in parallel with the clinical course of the development of HCCs in LEC rats. The pattern of c-jun mRNA augmentation was different from that of GST-P mRNA. These observations suggest that c-jun gene may play a role in the spontaneous development of HCCs in LEC rats.
Cancer Lett 1990 Sep
PMID:Increased expression of c-jun gene during spontaneous hepatocarcinogenesis in LEC rats. 197 34

Studies have suggested that the alpha class glutathione S-transferase (GST) may protect cells from the chemotherapeutic drugs chlorambucil and melphalan. In order to further define the function of human alpha class GST, a complementary DNA which encodes it was ligated into an expression vector under the direction of the human metallothionein-IIA promoter and stably transfected into human MCF-7 breast cancer cells in conjunction with the G418-selectable plasmid pSV2neo. Clonal cell lines were identified which expressed increased levels of GST enzyme activity (2.2- to 5.6-fold). The transfected cell lines also had increased peroxidase activity using cumene hydroperoxide as the substrate (1.9- to 3.8-fold) which is consistent with the intrinsic peroxidase activity of alpha class GSTs. Southern blot analysis indicated that genomic DNA from these cells contained a fragment indistinguishable from the transfected alpha class GST complementary DNA (850 base pairs); Northern blot analysis of total cellular RNA indicated that these cells contained appropriately sized alpha class GST RNA (980 nucleotides); and Western blot analysis indicated that, while MCF-7 cells contained no detectable alpha class GST protein, the transfected cells contained markedly elevated levels of alpha class GST but no detectable mu or pi class GST. These alpha class GST transfected cells had increased resistance to ethacrynic acid (2.1- to 3.0-fold). However, the transfected cells failed to show any increased resistance measured at the drug dosage which inhibited 50% of the colony formation to the chemotherapeutic drugs chlorambucil, melphalan, Adriamycin, or cisplatin under conditions of either continuous or 1-h drug exposure. Neither was there any change in sensitivity to the cytotoxins benzo(a)pyrene, benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (anti), or 1-chloro-2,4-dinitrobenzene. These studies indicate that expression of this human alpha class GST by itself in MCF-7 human breast cancer cells does not confer resistance to the chemotherapeutic drugs tested under the conditions used in these studies.
Cancer Res 1991 Jan 15
PMID:Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. 198 77

Four novel nontransformed epithelial cell lines, isolated from fetal or adult mouse liver, were tested: (a) to determine the profile of xenobiotic metabolizing enzymes; (b) to evaluate the inducibility of the polysubstrate (cytochrome P-450-dependent) monooxygenase system by various classes of inducers; and (c) to assess the capacity of the cells to metabolize structurally different procarcinogens. With regard to the phase I pathway, the cells expressed various P-450 (class IA, IA2, IIB, IIE1, IIIA) and flavin adenine dinucleotide-containing monooxygenase-dependent bio-transformation enzyme activities at levels (in lines C2.8 and C6) comparable with those present in murine adult liver preparations. The expression of various P-450s was demonstrated also by immunoprecipitation assays using rabbit polyclonal antibodies. For the phase II pathway, cells expressed substantial levels of glutathione S-transferase, glutathione S-epoxide transferase, and UDP-glucuronosyltransferase. Low expression of epoxide hydrolase was observed. Induction of P-450 function by sodium phenobarbital, beta-naphthoflavone, isosafrole, ethanol, and pregnenolone 16 alpha-carbonitrile, monitored using specific P-450-linked activities, was considerably elevated (over 5-fold in class IIB with the C2.8 and C6 cell lines). The most competent C2.8 and C6 cell lines were able to activate benzo(a)pyrene, cyclophosphamide, dimethylnitrosamine, diethylstilbestrol, and 2-naphthylamine as shown by the significantly increased frequencies of mitotic gene conversion, mitotic crossing-over, and point [reverse] mutation in the diploid D7 strain of Saccharomyces cerevisiae after 4 [cyclophosphamide], 24 [benzo(a)pyrene,2-naphthylamine, dimethylnitrosamine] or 48 [diethylstilbestrol], h of exposure in the presence of 3 x 10(6) cells/flask. The degree of conservation and the inducibility of representative oxidative and postoxidative reactions in the novel epithelial cell lines C2.8 and C6, together with their ability to activate a wide spectrum of procarcinogens, offers a means to study the potential of chemicals for inducing DNA damage in short-term genotoxicity testing. In addition the cells may be suitable for analyzing the metabolic disposition of compounds and the multistage process of carcinogenesis.
Cancer Res 1991 Jan 01
PMID:Expression and inducibility of drug-metabolizing enzymes in novel murine liver epithelial cell lines and their ability to activate procarcinogens. 198 92

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.
Cancer Res 1991 Jan 01
PMID:Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. 198 11


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