Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D00031 (Glutathione)
5,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs--the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferences and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes--acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.
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PMID:Mechanisms of multidrug resistance in cancer treatment. 135 55

Glutathione S-transferases (GSTs), a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents, can be separated by biochemical and immunologic characteristics into three distinct classes named alpha, mu, and pi. Previous studies have indicated that there is marked heterogeneity in the expression of different GST isoenzymes in different normal and malignant tissues. To better understand the regulation of the human pi class glutathione S-transferase isoenzyme (GST-pi), the tissue distribution of this protein wa studied by an immunohistochemical technique using an anti-GST-pi polyclonal antibody in normal paraffin-embedded human tissues. These studies indicate that there is a broad distribution of GST-pi in normal human tissues and establish a precise localization within the different organs studied. GST-pi was expressed predominantly in normal epithelial cells of the urinary, digestive, and respiratory tracts, suggesting a possible role for GST-pi in detoxication and elimination of toxic substances. Previous studies have indicated that GST-pi and the putative drug efflux pump P-glycoprotein are both overexpressed in multidrug-resistant human breast cancer cells and in xenobiotic resistant preneoplastic rat hyperplastic liver nodules. Results from this study indicate that there are also similarities between the normal tissue distribution GST-pi and that previously reported for mammalian P-glycoprotein, particularly in secretory epithelia. This finding suggests that these two gene products, which have been implicated in the development of resistance to cytotoxic drugs, may be coregulated in normal and malignant cells.
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PMID:An immunohistochemical study of pi class glutathione S-transferase expression in normal human tissue. 197 19

Wild-type MCF-7 human breast cancer cells were cultured for 3 months in 1 microM benzo[a]pyrene (BaP), and resistant clones were screened for inducibility of CYP1A1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One of the BaP-resistant (BaPR) clones exhibited unique genotypic expression which distinguished it from both wild-type and drug-resistant (AdrR) variant MCF-7 cells. Glutathione levels, glutathione S-transferase activities, estrogen receptor levels, estrogen responsiveness, and expression of the multidrug-resistant MDR1 and MRP mRNA levels were similar in the wild-type and BaPR cells, whereas these parameters were reported to be altered in AdrR cells. In contrast, TCDD induced CYP1A1 gene expression and inhibited selected estrogen-induced responses in wild-type but not BaPR MCF-7 cells. Treatment of wild-type and BaPR cells with [3H]TCDD resulted in formation of the radiolabeled aryl hydrocarbon (Ah) 6 S nuclear receptor complex in both cell lines. The loss of Ah responsiveness in the BaPR variant cells correlated with the failure of the nuclear or transformed cytosolic Ah receptor complex to bind genomic dioxin-responsive elements as determined in gel retardation assays.
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PMID:Benzo[a]pyrene-resistant MCF-7 human breast cancer cells. A unique aryl hydrocarbon-nonresponsive clone. 790 15

Glutathione (GSH) and glutathione S-transferases (GSTs) play an important role in the protection of cells against toxic effects of many electrophilic drugs and chemicals. Modulation of cellular GSH and/or GST activity levels provides a potentially useful approach to sensitizing tumor cells to electrophilic anti-cancer drugs. In this study, we describe the interactions of four representative alkylating agents (AAs), melphalan, 4-hydroperoxy-cyclophosphamide (4HC), an an activated form of cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and cisplatin, with GSH and GST in the human breast cancer cell line MCF-7. Depletion of cellular GSH pools by approximately 80% by treatment of the cells with the GSH synthesis inhibitor buthionine sulfoximine (BSO) sensitized the tumor cells to each AA to a different extent, with dose-modifying factors of 2.39, 2.21, 1.64, and 1.27 observed for melphalan, 4HC, cisplatin, and BCNU, respectively. Treatment of the cells with the GST inhibitor ethacrynic acid (EA) failed to show any significant effects on the cytotoxicity of these AAs. However, EA did potentiate the cytotoxicity of melphalan when given in combination with BSO, an effect that may be due to a more complete depletion of cellular GSH levels by the combined modulator treatment. Following a 1-hr exposure to cytotoxic-equivalent concentrations of these AAs, GSH levels decreased substantially in the case of 4HC and BCNU, but increased by 30-50% in the case of cisplatin and melphalan. BSO pretreatment largely blocked this effect of cisplatin and melphalan on cellular GSH, while it further enhanced the GSH-depleting activity of both 4HC and BCNU. On the basis of these results, it is concluded that (a) GSH affects the cytotoxicity of different AAs to different extents, (b) basal GST expression in MCF-7 cells does not play a major role in AA metabolism, (c) EA can potentiate the enhancing effect of BSO on melphalan cytotoxicity in MCF-7 cells, and (d) depletion of cellular GSH by pretreatment with BCNU or cyclophosphamide may correspond to a useful strategy for enhancing the anti-tumor activity of other AAs given in a sequential combination.
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PMID:Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. 814 7

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.
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PMID:Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. 833 60

Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy. Previous in-vitro and animal experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems. More specifically, an in-vitro assay showed that at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, Immunocal, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months. In six patients the blood lymphocyte GSH levels were substantially above normal at the outset, reflecting high tumour GSH levels. Two patients (#1, #3) exhibited signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease progressed with a trend toward higher lymphocyte GSH levels. These results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy.
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PMID:The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study. 866 40

Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine. The fact that some drug-resistant cell lines have increased GSH levels, and that enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. We previously showed a selective enhancement by the cysteine "pro-drug," L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of tumor-bearing rats, whereas there is a paradoxic GSH depletion in tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model. We have examined the OTZ "activating" enzyme, 5-oxoprolinase, in these tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in tumor in response to OTZ. A limited number of human breast cancer samples show similar activity.
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PMID:Modulation of glutathione by a cysteine pro-drug enhances in vivo tumor response. 878 49

A small increase in the risk of breast cancer has been reported after long term use of combined estrogen-progestagen treatment. Free oxygen radicals and antioxidants such as glutathione are involved in the regulation of proliferation and apoptosis and thereby in carcinogenesis. To study whether the glutathione levels are sex hormone dependent, we used the microdialysis technique to measure the in vivo concentrations of glutathione in breast tissue and sc fat during the menstrual cycle. Six healthy women (23-32 yr old) were investigated early in the follicular phase and the midluteal phase. Two 60-min fractions each were collected by microdialysis of periumbilical fat and breast tissue, respectively. The samples were stored at -70 C and analyzed by high performance liquid chromatography. Glutathione concentrations increased in the midluteal phase compared to those in the follicular phase in both adipose tissue and breast tissue (P < 0.05). The variability of glutathione levels during the menstrual cycle, with higher levels late in the menstrual cycle, indicates that the antioxidant system could be sex hormone dependent. This may be of importance in breast cancer development.
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PMID:Variability of glutathione levels in normal breast tissue and subcutaneous fat during the menstrual cycle: an in vivo study with microdialysis technique. 914 20

Glutathione S-transferases mu (GSTM) are dimeric cytosolic isoenzymes. They catalyze glutathione conjugation upon a large variety of electrophiles as carcinogens, trans-stilbene peroxide or benzo(a)pyrene. The gene GSTM1 is localized on chromosome 1p13, it has drawn attention because it is absent approximately in 50% of the white population. GSTM1 null genotype seems linked with susceptibility to cancers as lung, colon and bladder cancers. We have studied GSTM1 genotype from 373 primary breast tumours. The GSTM1 null genotype was found in 50% of the cases (185/373). The incidence study of GSTM1 copy number on clinical and biological variables displayed a significant difference (p < 0.01) of the GSTM1 genotype, showed by the tumour, according to the patient age at diagnosis. The patients younger than 55 years had a percentage more important of primary tumours (65%) with a copy number of GSTM1 gene, inferior or equal at one, compared to the patients older than 55 years (52%). The tumours, whose cathepsin D level was high, presented few copies of GSTM1 gene (p < 0.03). There was no other relationship, particularly, with tumour size, node status, histological type, hormonal receptors, pS2 cytosolic level GSTM1 gene seems protect the mammary gland from cancerogenesis with its detoxification role. This results had not, pointed out in breast cancer, yet.
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PMID:[Glutathione S-transferase mu 1 (GSTM1): susceptibility gene of breast cancer]. 918 Aug 57

Many reports indicate that glutathione and enzymes cooperating with it are important in neoplastic processes. Glutathione (GSH) concentrations and glutathione S-transferase (GSH STr) and glutathione peroxidase (GSH-Px) activities were determined in breast cancer tissue and adjacent healthy tissues, as well as in blood of 28 patients. There were considerable differences in the investigated parameters among individual patients. Therefore we analyzed the paired samples of normal and cancerous tissues from the same individual. In 68% of the patients the activities of GSH-Px and in 85% patients those of GSH STr were found to be higher in the tumor than in the normal tissue. GSH concentration in 48% tumor samples were higher and in 44% lower than in corresponding normal tissues. Statistically significant correlation was found between GSH-Px and GSH STr in normal (r = 0.51, p < 0.005) and in cancer tissues (r = 0.64, p = 0.001). Correlation coefficient between GSH Px activity in normal and corresponding cancer tissues was r = 0.71 (p < 0.001), however this correlation in the case of GSH STr was much lower but still significant (r = 0.38, p < 0.05). No significant correlation in the determined parameters was found between erythrocytes or plasma and normal or cancer tissues.
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PMID:Glutathione and glutathione metabolizing enzymes in tissues and blood of breast cancer patients. 920 Dec 80


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