Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A spontaneously originated murine mammary adenocarcinoma (16C), selected for its sensitivity to agents active against breast cancer in women, and one of the very few experimental solid tumor models responsive to Adriamycin (ADR) was used to study the mechanism of induced ADR resistance in vivo. A resistant variant of the tumor was obtained from the explant of a regrown tumor following a dose of ADR (12 mg/kg) that caused complete tumor repression but not cure. Progressive refractoriness to ADR was observed following up to six repeated cycles of treatment, regression and regrowth. However, beyond the sixth treatment, no further degree of resistance could be obtained. The cell line so established, designated 16C/ADRR, has a glutathione (GSH) content 1.67 times greater than the parent 16C line. Depletion of GSH by buthionine sulfoximine (BSO) enhanced the cytoxicity of ADR in both cell lines. The sensitization effect appeared to be dependent on the degree of GSH depletion, requiring a threshold level of depletion to approximately 30% of control. The resistance of 16C/ADRR, however, appeared not to be directly related to the increased absolute GSH level per se since reduction of the GSH content of the 16C/ADRR line to levels similar to that of the parent 16C line did not restore the original sensitivity to ADR. However, the activities of two important elements in the GSH detoxification system, GSH peroxidase and S-transferase, were found to be elevated in resistant cells by factors of 2.4 and 4.7-5.6 respectively. In vivo studies with a diverse spectrum of antineoplastic drugs revealed a pattern of cross-resistance consistent with the idea that elevated GSH S-transferase and peroxidase activities may be responsible for the decreased (2.8- to 5.3-fold) sensitivity to ADR. 16C/ADRR exhibited cross-resistance with melphalan (MEL), but none with vincristine (VCR), vinblastine (VBL) or etoposide (VP-16). These results clearly demonstrate non-adherence by the 16C/ADRR tumors to the well characterized multidrug resistance (mdr) phenotype. Further affirmation of this conclusion was obtained by immunochemical and pharmacological studies. When a monoclonal antibody prepared against the mdr associated, 170 kD P-glycoprotein (170 P-gp), was used, the presence of the 170 kD P-gp in both the sensitive and resistant 16C lines could not be detected, although the presence of a lower molecular weight form of P-gp could not be ruled out entirely. High performance liquid chromatographic measurement of ADR accumulation and elimination also failed to reveal any significant differences between the sensitive and resistant variants.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:A study of the mechanism of resistance to Adriamycin in vivo. Glutathione metabolism, P-glycoprotein expression, and drug transport. 257 74

The aims of our experiments were to clear up the possible correlations between the free radical mechanisms and the gastric cytoprotection of beta-carotene on HCl-induced gastric mucosal lesions. The beta-carotene was intragastrically given in doses of 1 and 10 mg/kg and 30 min. later 1 ml 0.6 N HCl was given to provoke the mucosal damage. After 1, 5, 15, 30 and 60 min. the animals were sacrificed. The number and severity of gastric mucosal lesions were calculated. The superoxide dismutase (SOD), glutathion peroxidase (GPX), catalase (CAT) activity and the malondialdehyde (MDA) and reduced glutathion (GSH) contents were determined from the gastric mucosa of rats. It was found that 1. beta-carotene was able to reduce the number and severity of ulcers only after 30 min.; 2. the CAT activity was decreased at 60 min. by carotene; 3. the GPX activity became dissimilar in the different groups after 15 min; 4. the changes of GSH were found to be similar ones; 5. the SOD activity was lower during the cyto-protection; 6. the MDA level remained practically unchanged. It has been concluded that 1. the free radicals are the consequences of the development of gastric ulcer and cytoprotection; 2. the scavenger character of beta-carotene is involved in its cytoprotective effect.
 ...
PMID:The free radical mechanisms in beta-carotene induced gastric cytoprotection in HCl model. 259 22

Glutathione (GSH) comprises the bulk of the pool of free thiol groups in biological systems. Since its first description as philothione 100 years ago, there have been repeated surprises in discoveries of novel functions. Just recently the important role of thioethers with products of the lipoxygenase reaction, i.e., the leukotrienes, was revealed as mediator of physiological and pathophysiological processes. Another major function resides in detoxication, GSH being cosubstrate in the GSH-peroxidase reaction for the reduction of hydroperoxides in the defense against oxidative stress. Interest also focuses on reactions of glutathionyl radicals in protection by thiols against DNA damage resulting from ionizing radiation.
 ...
PMID:[Biochemistry of thiol groups: the role of glutathione]. 265 38

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
 ...
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Human platelets were dose- and time-dependently depleted of intracellular glutathione (GSH) by treatment with the chemical oxidizing agents diamide and N-ethylmaleimide (NEM), and by formation of chemical conjugates with 1-chloro-2,4-dinitrobenzene (CDNB) catalyzed by GSH-S-transferase. In addition to effects upon GSH, these agents also inhibited platelet GSH-peroxidase activity. The inhibitory effect of CDNB was selective for GSH-peroxidase, while diamide and NEM treatment caused inhibition of several other cytosolic enzymes tested. Arachidonic acid (AA) induced aggregation and secretion responses measured in platelets depleted of GSH by diamide and NEM were attenuated. In contrast, these platelet functions remained identical to control following GSH depletion by CDNB treatment, suggesting that GSH is not required for normal platelet aggregation or secretion. Effects of diamide and NEM apart from their action on GSH may account for the platelet dysfunction induced by these compounds.
 ...
PMID:The influence of glutathione depleting agents on human platelet function. 273 29

The pathogenesis of neonatal necrotizing enterocolitis is unknown, but a possible role for reactive oxygen metabolites has been postulated. We evaluated whether developmental differences exist in the levels of 1) the free radical-generating enzyme xanthine oxidase, 2) granulocyte peroxidase, an index of the resident granulocyte population, 3) free radical-scavenging enzymes (superoxide dismutase, catalase, and glutathione peroxidase), and 4) reduced glutathione, an endogenous antioxidant, in the ileal and colonic mucosa of 1-d-old, 3-d-old, 2-wk-old, and 1-mo-old piglets. We found no xanthine dehydrogenase/oxidase activity in 1-d to 1-mo-old piglets. Mucosal granulocyte peroxidase activity was higher in older animals, indicating that there was an age-dependent infiltration of granulocytes (eosinophils, neutrophils) in the distal bowel. The peroxidase activity per circulating granulocyte, however, did not vary with age. Superoxide dismutase activity was significantly higher in 1-d-old piglets than in all older age groups; glutathione peroxidase activity was significantly lower in 1-d-old animals than that of older age groups. There was no detectable catalase activity in the mucosa when tissue was corrected for catalase activity of blood. Finally, ileal GSH levels were significantly lower in 1-d-old than in 2-wk-old and 1-mo-old animals, whereas colonic reduced glutathione activity did not differ among age groups. In conclusion, the distal bowel of the neonatal piglet appears to have a limited capacity to generate oxidants via xanthine oxidase and resident granulocytes. However, the neonatal piglet intestine has a lower capacity to detoxify hydrogen peroxide than that of older animals.
 ...
PMID:Developmental biology of oxidant-producing enzymes and antioxidants in the piglet intestine. 274 Jan 52

Inhibition of the enzyme activity of glutathione S-transferase (GST) by a physiological concentration of bilirubin was studied using various substrates. When rat liver cytosol was used as an unfractionated GST, its GSH-conjugation activity toward 1-chloro-2,4-dinitrobenzene was decreased to one-half by bilirubin, while the activity toward 1,2-dichloro-4-nitrobenzene, p-nitrobenzyl chloride, or 1,2-epoxy-(p-nitrophenoxy)propane and also the non-selenium dependent GSH-peroxidase activity toward cumene hydroperoxide (CHPx activity) were hardly affected under the same conditions. In contrast, bilirubin inhibited each of the purified GST isozymes and no remarkable difference in bilirubin inhibition was observed with any of the substrates tested. From the chromatographic analysis of the cytosol incubated with [3H]bilirubin, it was found that a major part of the added bilirubin binds to subunit 1 (Ya) of GST isozyme, leaving not only the conjugation activity derived from 3-4 type GST but also the CHPx activity of subunit 2 (Yc) quantitatively intact. The bilirubin inhibition of both the conjugation activity of GST 3-4 and the CHPx activity of GST 2-2 was prevented almost completely by addition of a 3-fold molar excess of GST 1-1. From these results, it was assumed that the enzyme activities of both 3-4 type GSTs and subunit 2 (Yc) were protected from the inhibitory action of bilirubin by the scavenger effect of subunit 1 (Ya).
 ...
PMID:Protection of glutathione S-transferase from bilirubin inhibition. 276 23

This study investigates the effects of 3 successive cisplatin administrations on rat kidney cytochrome P-450 and drug-metabolizing enzyme activities. Furthermore, because glutathione (GSH) and its related enzymatic system are involved in cellular detoxification processes, we examined the effects of cisplatin on lipid peroxidation, GSH levels, and GSH reductase and peroxidase activities. Cisplatin induced a decrease in cytochrome P-450, GSH, GSH S-transferase, GSH reductase and GSH peroxidase activities, and an increase in N-glucuronyl transferase, lipid peroxidation and oxidized glutathione (GSSG) in kidney cortical microsomes and cytosolic fractions. It is suggested that cisplatin nephrotoxicity could be explained by its affinity for SH-groups of several enzymes and SH-containing compounds. Among these, GSH and its related enzymatic system play a primary role. Moreover, cisplatin increases lipid peroxidation, which might participate in cisplatin nephrotoxicity.
 ...
PMID:Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzyme activities in rat kidney cortex. 277 25

Ascorbate-Fe3+-induced and NADPH-induced lipid peroxidation of rat liver microsomes were inhibited by glutathione (GSH). This inhibition was due to microsomal GSH-dependent factor. This factor was heat labile, and storage of microsomes at 4 degrees C for 1 week diminished the activity. GSH could not be substituted by other sulfhydryl compounds tested. Deoxycholate (1 mM) and bromosulfophthalein (0.1 mM) inhibited GSH-dependent protection but did not inhibit microsomal GSH peroxidase activity. Iodoacetate (10 mM) inhibited GSH-dependent protection but did not inhibit microsomal GSH S-transferase. N-Ethylmaleimide (0.1 mM) and oxidized glutathione (10 mM) inhibited GSH-dependent protection but activated microsomal GSH S-transferase activity. These results indicate the existence of a heat-labile, microsomal GSH-dependent protective factor against lipid peroxidation that acts through a factor other than GSH-peroxidase and GSH S-transferase.
 ...
PMID:Microsomal glutathione-dependent protection against lipid peroxidation acts through a factor other than glutathione peroxidase and glutathione S-transferase in rat liver. 277 85

Diethyldithiocarbamate (DDTC) injected i.p. inhibits remarkably and in a dose-dependent manner 12-O-tetradecanoylphorbol-13-acetate (TPA)-decreased glutathione (GSH) peroxidase and TPA-induced ornithine decarboxylase (ODC) activities in mouse epidermis in vivo. DDTC is more potent in inhibiting these effects of TPA than 16 other antioxidants, free radical scavengers, thiol-containing compounds, and reduced glutathione (GSH) level-raising agents, even though some of these treatments are applied directly to the TPA-treated skin. DDTC also inhibits the effects of several structurally different tumor promoters and the greater GSH peroxidase and ODC responses produced by repeated TPA treatments. The inhibitory effects of DDTC on TPA-decreased GSH peroxidase and TPA-induced ODC activities are additive with those of Na2SeO3 and D-alpha-tocopherol (vitamin E). Interestingly, DDTC is a more effective inhibitor when it is administered after TPA, suggesting that DDTC may supplement, facilitate, and/or enhance the activity of the natural GSH-dependent detoxifying system protecting the epidermis against the oxidative challenge presumably linked to the tumor-promoting activity of TPA. When tested in the initiation-promotion protocols, DDTC inhibits to the same degree complete tumor promotion by TPA and stage 2 tumor promotion by mezerein, in relation with its identical inhibition of the GSH peroxidase and ODC responses to both TPA and mezerein. Moreover, the inhibition of the first stage tumor-promoting activity of TPA by DDTC may be attributed to its ability to inhibit TPA-induced DNA synthesis, a postulated component of the conversion phase of skin carcinogenesis when TPA is used as a stage 1 tumor promoter.
 ...
PMID:Inhibition of multistage tumor promotion in mouse skin by diethyldithiocarbamate. 282 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>