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PubMed1990

Enhanced depletion of lens reduced glutathione Adriamycin in riboflavin-deficient rats.

The anticancer drug Adriamycin has photosensitizing properties which potentially may be detrimental to lens tissue. Since reduced glutathione (GSH) serves to protect lens from photo-oxidative stress and dietary riboflavin is required by glutathione reductase to regenerate GSH, we investigated whether Adriamycin intensifies the depletion of GSH levels in rat lens during dietary riboflavin deficiency. Three-week-old rats were divided into two groups. One group was fed a diet deficient in riboflavin (less than 1 ppm) and the other group was pair-fed a control diet containing adequate riboflavin (8.5 ppm). After 6-12 weeks of dietary treatment, half the animals in each dietary group received Adriamycin (8 mg/kg/day) intraperitoneally for 3 days. After killing the rats, lenses were removed, and GSH content and glutathione reductase activity were measured in freshly prepared homogenates. To determine the extent of systemic oxidative stress and the degree of riboflavin deficiency, glucose-6-phosphate dehydrogenase and glutathione reductase activities, respectively, were measured in erythrocytes. In lens of rats fed the riboflavin-sufficient diet, treatment with Adriamycin did not diminish GSH content or alter glutathione reductase activity. In confirmation of reports by others, lenses of animals fed the riboflavin-deficient diet had diminished GSH levels, lower basal glutathione reductase activity, and elevated glutathione reductase activity coefficients compared to those of animals pair-fed the control diet. The present study shows that in riboflavin-deficient rats, Adriamycin exacerbated the depletion of GSH but did not reduce further glutathione reductase activity. The implications of these findings are that nutritional deficiencies, in particular riboflavin deprivation, may pose a potential risk to lenticular tissue following Adriamycin treatment.

Animals↗

PubMed1981

Riboflavin status in Gambian pregnant and lactating women and its implications for Recommended Dietary Allowances.

Riboflavin status by the erythrocyte glutathione reductase (NAD(P)H2:glutathione oxidoreductase EC1.6.4.2) test, and dietary riboflavin intake, were measured in 156 pregnant and lactating women in Keneba, a rural Gambian village, and in 59 pregnant and lactating women in Cambridge, England. The Keneba women were studied longitudinally, for up to 19 months. In Keneba, where the mean daily riboflavin intake was 0.5 mg, the mean erythrocyte glutathione reductase activation coefficient was 1.78 and there was a marked deterioration of biochemical status near parturition. In Cambridge, where the mean intake was 2.3 mg/day, the mean activation coefficient was 1.19. A vitamin fortified diet supplement, given to lactating women in Keneba for 8 months, raised their mean riboflavin intake for 0.5 to 1.5 mg/day and reduced the mean activation coefficient to 1.42. It is therefore likely that an intake even greater than the current United Kingdom or United States recommended daily amounts would be needed to achieve biochemical 'normality' in these women.

Adolescent↗

PubMed1989

Effect of hyperoxia on antioxidants in neonatal rat type II cells in vitro and in vivo.

Relative resistance to oxygen toxicity in newborn animals (compared to adults) has been associated with increased antioxidant enzymes and glutathione in lung homogenate. The cell type(s) involved in this increase is unknown. We investigated the effect of hyperoxia in vitro and in vivo on the following antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and glutathione) in alveolar type II cells from neonatal rats. Type II cells were exposed to 95% oxygen or air for 48 h in vitro. When expressed per microgram DNA, all the antioxidants except catalase increased during in vitro incubation; only glucose-6-phosphate dehydrogenase and glutathione increased when expressed per mg protein. None of the antioxidants was higher in oxygen-exposed cells than in air-exposed cells. Neonatal rats were exposed to 100% oxygen or air in vivo for 4 d before determination of antioxidants in lung homogenate supernatant and alveolar type II cells. Catalase, glutathione peroxidase, and glutathione reductase were higher but glucose-6-phosphate dehydrogenase and glutathione were lower in type II cells than in lung homogenate from control animals. Alveolar type II cell glucose-6-phosphate dehydrogenase and glutathione were increased but catalase and glutathione reductase were decreased by exposure to hyperoxia. We conclude that the oxygen-induced increase in whole lung antioxidants is not explained by alveolar type II cell hypertrophy or increased antioxidants within type II cells during hyperoxia.

Animals↗

PubMed2004

Platelet surface glutathione reductase-like activity.

We previously found that reduced glutathione (GSH) or a mixture of GSH/glutathione disulfide (GSSG) potentiated platelet aggregation. We here report that GSSG, when added to platelets alone, also potentiates platelet aggregation. Most of the GSSG was converted to GSH by a flavoprotein-dependent platelet surface mechanism. This provided an appropriate redox potential for platelet activation. The addition of GSSG to platelets generated sulfhydryls in the beta subunit of the alpha(IIb)beta(3) fibrinogen receptor, suggesting a mechanism for facilitation of agonist-induced platelet activation.

Blood Platelets↗

PubMed1987

Formation and reduction of glutathione-protein mixed disulfides during oxidative stress. A study with isolated hepatocytes and menadione (2-methyl-1,4-naphthoquinone).

Incubation of isolated rat hepatocytes with menadione (2-methyl-1,4-naphthoquinone) resulted in a dose-dependent depletion of intracellular reduced glutathione (GSH), most of which was oxidized to glutathione disulfide (GSSG). Menadione metabolism was also associated with a dose- and time-dependent inhibition of glutathione reductase, impairing the regeneration of GSH from GSSG produced during menadione-induced oxidative stress. Inhibition of glutathione reductase by pretreatment of hepatocytes with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) greatly potentiated both GSH depletion and GSSG formation during the metabolism of low concentrations of menadione. Concomitant with GSH oxidation, mixed disulfides between glutathione and protein thiols were formed. The amount of mixed disulfides produced and the kinetics of their formation were dependent on both the intracellular GSH/GSSG ratio and the activity of glutathione reductase. The mixed disulfides were mainly recovered in the cytosolic fraction and, to a lesser extent, in the microsomal and mitochondrial fractions. The removal of glutathione from protein mixed disulfides formed in hepatocytes exposed to oxidative stress was dependent on GSH and/or cysteine and appeared to occur predominantly via a thiol-disulfide exchange mechanism. However, incubation of the microsomal fraction from menadione-treated hepatocytes with purified glutathione reductase in the presence of NADPH also resulted in the reduction of a significant portion of the glutathione-protein mixed disulfides present in this fraction. Our results suggest that the formation of glutathione-protein mixed disulfides occurs as a result of increased GSSG formation and inhibition of glutathione reductase activity during menadione metabolism in hepatocytes.

Animals↗

PubMed2000

Physiological functions of thioredoxin and thioredoxin reductase.

Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ubiquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast thioredoxins, which via ferredoxin-thioredoxin reductase regulates photosynthetic enzymes by light. Thioredoxins are critical for redox regulation of protein function and signaling via thiol redox control. A growing number of transcription factors including NF-kappaB or the Ref-1-dependent AP1 require thioredoxin reduction for DNA binding. The cytosolic mammalian thioredoxin, lack of which is embryonically lethal, has numerous functions in defense against oxidative stress, control of growth and apoptosis, but is also secreted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants with a redox active site disulfide/dithiol. In contrast, thioredoxin reductases of higher eukaryotes are larger (112-130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisulfide substrates such as hydroperoxides, vitamin C or selenite. All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.

Amino Acid Sequence↗

PubMed1992

Effect of L-penicillamine hydantoin, an analogue of glutathione, on rat liver glutathione peroxidase, reductase and transferase reactions.

In soluble fractions prepared from rat liver homogenates, L-penicillamine hydantoin appeared to be, on the basis of SH consumption measurements, a substrate for glutathione peroxidase but not transferase reactions. When glutathione is incubated with rat liver soluble proteins in the presence of penicillamine hydantoin, formation of oxidized glutathione is inhibited. Calculations from Lineweaver-Burk plots point out that inhibition by L-penicillamine hydantoin of the peroxide-dependent oxidations of glutathione is mixed, since both apparent Km and Vmax values are modified. Preincubation of rat liver soluble proteins with L-penicillamine hydantoin led to a progressive inactivation of glutathione peroxidase. The kinetics of this inactivation process with respect to time and inactivator concentration were studied. Inclusion in the preincubation mixture of SH-containing molecules such as dithiothreitol, L-cysteine or glutathione protected the enzyme against inactivation. However, none of these molecules and neither hydantoin, Triton X-100, phenol, nor dialysis could reverse the enzyme from inactivated to activated form. Mitochondrial glutathione peroxidase was inhibited and inactivated by L-penicillamine hydantoin to the same extent as its cytosolic counterpart. Modifications by penicillamine hydantoin of various subcellular markers enzymes (lactate dehydrogenase, N-acetyl beta-glucosaminidase, arylsulfatase C, butyryl-CoA dehydrogenase, lauryl-CoA and glycolate oxidases) were of weak amplitude consisting of either inhibition, inactivation or stimulation.

Animals↗

PubMed1989

2-Bromohydroquinone-induced toxicity to rabbit renal proximal tubules: evidence against oxidative stress.

2-Bromohydroquinone (BHQ) plays an important role in bromobenzene-induced nephrotoxicity and is a model toxic hydroquinone. Since BHQ has a quinone nucleus and various quinones have been shown to produce cytotoxicity via oxidative stress, the goal of this study was to determine whether BHQ produced cytotoxicity in a suspension of rabbit renal proximal tubules via oxidative stress. t-Butyl hydroperoxide (TBHP), an agent known to produce cytotoxicity via oxidative stress in this preparation, was used as a positive control. BHQ decreased tubular glutathione disulfide content whether glutathione reductase was inhibited or not. Inhibition of glutathione reductase did not result in the potentiation of BHQ-induced mitochondrial dysfunction or cell death. In contrast, TBHP increased tubular glutathione disulfide content. TBHP-induced increases in glutathione disulfide content, mitochondrial dysfunction, and cell death were potentiated when glutathione reductase was inhibited. Unlike TBHP, BHQ did not initiate lipid peroxidation nor was the antioxidant butylated hydroxytoluene protective. However, BHQ and TBHP both increased sodium cyanide-insensitive oxygen consumption. These results suggest that BHQ may undergo "redox cycling," but BHQ-induced mitochondrial dysfunction and cell death are not due to oxidative stress.

Animals↗

PubMed2001

Purification and characterization of glutathione conjugate reductase: a component of the tetrachlorohydroquinone reductive dehalogenase system from Phanerochaete chrysosporium.

A membrane-bound glutathione S-transferase and a soluble glutathione conjugate reductase constitute the reductive dehalogenase system of P. chrysosporium. This enzyme system reductively removes chlorine substituents from tetrachlorohydroquinone, a metabolite of pentachlorophenol. The membrane-bound glutathione S-transferase converts tetrachlorohydroquinone to S-glutathionyltrichloro-1,4-hydroquinone, which is subsequently reduced to 3,5,6-trichlorohydroquinone by the soluble glutathione conjugate reductase (GCR). This GCR can accept glutathione, dithiothreitol, cysteine, or beta-mercaptoethanol as cosubstrates. GCR was purified to apparent homogeneity by ion-exchange and covalent chromatography. The enzyme exhibits optimum activity at pH 6.0 and 55 degrees C and appears to be a homodimer with a M(r) of approximately 60 kDa. Activity increases as the number of chlorine substituents on the hydroquinone ring is increased. GCR has an apparent K(m) of approximately 33 microM and an apparent k(cat) of approximately 3.43 s(-1) for 2-S-glutathionyl-3,5,6-trichloro-1,4-hydroquinone. Inhibitors of GCR include Cd(2+), Fe(2+), Mn(2+), iodoacetic acid, and p-chloromercuribenzoic acid, suggesting the presence of a catalytic cysteine thiol(s) at the active site. When glutathione is used as a cosubstrate, reduction of S-glutathionyltrichloro-1,4-hydroquinone is accompanied by the production of trichlorohydroquinone and oxidized glutathione in a 1:1 ratio. A mechanism for this novel enzyme is proposed.

Glutathione↗

PubMed1996

Chilling, oxidative stress and antioxidant responses in Arabidopsis thaliana callus.

Chilling of Arabidopsis thaliana (L.) Heynh. callus tissue to 4 degrees C led to conditions of oxidative stress, as indicated by increased levels of the products of peroxidative damage to cell membranes. Cellular H2O2 was also observed to increase initially upon chilling but by day 8 cellular levels had declined to below control levels. Although levels of catalase activity remained similar to those in unchilled tissue, activity of ascorbate peroxidase increased between days 4 and 8 of chilling to 4 degrees C. In callus held at 23 degrees C, levels of reduced glutathione remained static whereas they rose in callus held at 4 degrees C. Levels of oxidised glutathione were initially low but increased significantly by day 4 in the chilled callus. At 23 degrees C, however, levels of oxidised glutathione remained low. Between days 1 and 3 at 4 degrees C, levels of glutathione reductase activity increased but by day 8 glutathione reductase activity was similar to that in cells held at 23 degrees C. Exposure of callus to abscisic acid at 23 degrees C also led to increased activities of ascorbate peroxidase and glutathione reductase.

Antioxidants↗

PubMed1997

Evidence for a functional relevance of the selenocysteine residue in mammalian thioredoxin reductase.

Human thioredoxin reductase was recently shown to contain a TGA encoded selenocysteine residue at the penultimate position of its amino acid chain. Depending on the availability of selenium during biosynthesis, an authentic selenocysteine-containing or a selenium-free enzyme truncated at the penultimate position is expected to be formed. Correspondingly, the enzymatic activity should be altered by selenium restriction, if the selenocysteine residue is functionally important. In order to check the catalytic role of the selenocysteine residue, four different human cell lines were grown in selenium deficient media or with adequate selenium supplementation (40 nM sodium selenite) and thioredoxin reductase activity was measured as NADPH-dependent DTNB reduction or thioredoxin-mediated insulin reduction. Thioredoxin reductase activities, like glutathione peroxidase activities, were consistently higher in selenium supplemented cells, whereas glutathione reductase activity was not affected by the selenium. The dose-response was similar for thioredoxin reductase and glutathione peroxidase, but the recovery of glutathione peroxidase activity upon selenium supplementation was faster than with thioredoxin reductase. Also the increase of glutathione peroxidase activities was substantially higher than that of thioredoxin reductase (400-1200% versus a maximum of 250%). These observations clearly indicate a catalytic role of the selenocysteine residue in the thioredoxin reductase, but suggest either the existence of a selenium-unresponsive isoenzyme or a residual disulfide reductase activity in the selenium-free truncated protein made under conditions of selenium deficiency.

Animals↗

PubMed1993

Mechanisms of protection from menadione toxicity by 5,10-dihydroindeno[1,2,-b]indole in a sensitive and resistant mouse hepatocyte line.

Established cell lines derived from newborn livers of c14CoS/c14CoS and cch/cch mice have been shown to be genetically resistant (14CoS/14CoS cells) or susceptible (ch/ch cells) to menadione toxicity. These differences are due in part to relatively higher levels of reduced glutathione (GSH) and NAD(P)H:menadione oxidoreductase (NMO1) activity in the 14CoS/14CoS cells. The indolic membrane-stabilizing antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII) was shown previously to protect against various hepatotoxicants in vivo and in primary rat hepatocytes. This report describes how the 14CoS/14CoS and ch/ch cell lines provide a valuable experimental system to distinguish the mechanism of chemoprotection by DHII from menadione toxicity. The addition of 25 microM DHII produced a time-dependent decrease in menadione-mediated cell death in 14CoS/14CoS cells, with little effect on ch/ch cell viability. The maximum protective effect occurred at 24 hr, although the concentration of DHII remained constant for 48 hr. The protective effect of DHII correlated with enhanced glutathione levels (234% increase at 24hr), as well as induction of four enzymes involved in the detoxification and excretion of menadione: NAD(P)H:menadione oxidoreductase (NMO1, quinone reductase), glutathione reductase, glutathione transferase (GST1A1), and UDP glucuronosyltransferase (UGT1*06), with 24-hr maximum induction of 707, 201, 171 and 198%, respectively. Other biotransformation enzymes not directly involved in menadione metabolism (glutathione peroxidase, cytochromes P4501A1 and P4501A2, copper-, zinc-dependent superoxide dismutase, and NADPH cytochrome c oxidoreductase) were not induced by DHII. Menadione-stimulated superoxide production was inhibited 50% by DHII only in 14CoS/14CoS cells, and the inhibition required 24-hr preincubation. Pretreatment with DHII also protected both cell types against the menadione-mediated depletion of GSH, and the increase in percent (oxidized glutathione GSSG), an indicator of oxidative stress. These results suggest that DHII does not protect against menadione toxicity by virtue of its antioxidant or membrane-stabilizing properties. Rather, it acts by inducing a protective enzyme profile that migates redox cycling and facilitates excretion of menadione.

Animals↗

PubMed2003

Glutathione protects Lactococcus lactis against oxidative stress.

Glutathione was found in several dairy Lactococcus lactis strains grown in M17 medium. None of these strains was able to synthesize glutathione. In chemically defined medium, L. lactis subsp. cremoris strain SK11 was able to accumulate up to approximately 60 mM glutathione when this compound was added to the medium. Stationary-phase cells of strain SK11 grown in chemically defined medium supplemented with glutathione showed significantly increased resistance (up to fivefold increased resistance) to treatment with H2O2 compared to the resistance of cells without intracellular glutathione. The resistance to H2O2 treatment was found to be dependent on the accumulation of glutathione in 16 strains of L. lactis tested. We propose that by taking up glutathione, L. lactis might activate a glutathione-glutathione peroxidase-glutathione reductase system in stationary-phase cells, which catalyzes the reduction of H2O2. Glutathione reductase, which reduces oxidized glutathione, was detectable in most strains of L. lactis, but the activities of different strains were very variable. In general, the glutathione reductase activities of L. lactis subsp. lactis are higher than those of L. lactis subsp. cremoris, and the activities were much higher when strains were grown aerobically. In addition, glutathione peroxidase is detectable in strain SK11, and the level was fivefold greater when the organism was grown aerobically than when the organism was grown anaerobically. Therefore, the presence of glutathione in L. lactis could result in greater stability under storage conditions and quicker growth upon inoculation, two important attributes of successful starter cultures.

Culture Media↗

PubMed2004

Antioxidant status of red blood cells and liver in hypercholesterolemic rats fed hypolipidemic spices.

Animal studies were carried out to examine the beneficial influence of known hypolipidemic spice principles--curcumin, capsaicin, and garlic--on the antioxidant status of red blood cells and liver under induced hypercholesterolemic conditions. Groups of experimental rats rendered hypercholesterolemic were maintained on curcumin (0.2%)/capsaicin (0.015%)/garlic (2.0% dry powder)-containing diets for eight weeks. Erythrocytes isolated at the end of the study were analyzed for intracellular antioxidant molecules and antioxidant enzymes. Intracellular thiols and glutathione content in red blood cells were significantly depleted (by about 35%) in hypercholesterolemic rats. This depletion in intracellular thiols and glutathione was effectively countered by dietary spice principles - curcumin, capsaicin, and garlic. Glutathione reductase activity that was lowered in hypercholesterolemic conditions (by 25%) was completely countered by dietary spice principles and garlic. Activities of glutathione transferase, glutathione peroxidase, and catalase in erythrocytes remained unchanged under hypercholesterolemic conditions. Although hemoglobin levels of erythrocytes were not affected, methemoglobin concentration was significantly increased in hypercholesterolemic rats. This alteration was partially countered by dietary spice principles. Significant fall in hepatic total thiols in the hypercholesterolemic situation was partially corrected by dietary spice treatment. Similarly, the lowered activities of hepatic antioxidant enzymes--glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase--in hypercholesterolemic rats were effectively countered by the dietary spices treatment.

Animals↗

PubMed2005

Protective effects of zinc on oxidative stress enzymes in liver of protein-deficient rats.

Persons afflicted with protein malnutrition are generally deficient in a variety of essential micronutrients like zinc, copper, iron, and selenium, which in turn affects number of metabolic processes in the body. To evaluate the protective effects of zinc on the enzymes involved in oxidative stress induced in liver of protein-deficient rats, the current study was designed. Zinc sulfate at a dose level of 227 mg/L zinc in drinking water was administered to female Sprague-Dawley normal control as well as protein-deficient rats for a total duration of 8 weeks. The effects of zinc treatment in conditions of protein deficiency were studied on rat liver antioxidant enzymes, which included catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), glutathione reduced (GSH), and glutathione-S-transferase (GST). Protein deficiency in normal rats resulted in a significant increase in hepatic activities of catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and the levels of lipid peroxidation. A significant inhibition in the levels of reduced glutathione and the enzyme activity of superoxide dismutase has been observed after protein deficiency in normal rats. Interestingly, Zn treatment to protein-deficient animals lowered already raised activity catalase, glutathione peroxidase, and glutathione-S-transferase and levels of lipid peroxidation to significant levels when compared to protein-deficient animals. Also, Zn treatment to the protein-deficient animals resulted in a significant elevation in the levels of GSH and SOD activity as compared to their respective controls, thereby indicating its effectiveness in regulating their levels in adverse conditions. It has also been observed that concentrations of zinc, copper, iron, and selenium were found to be decreased significantly in protein-deficient animals. However, the levels of these elements came back to within normal limits when zinc was administrated to protein-deficient rats. This study concludes that zinc has the potential to regulate the activities of oxidative stress enzymes as well as essential hepatic elements.

Animals↗

PubMed1996

Transforming growth factor-beta in in vivo resistance.

The potential role of transforming growth factor-beta in in vivo resistance was examined by administration of transforming growth factor-beta-neutralizing antibodies to animals bearing the EMT-6/Parent tumor or the antitumor alkylating resistance tumors, EMT-6/CTX or EMT-6/CDDP. Treatment of tumor bearing animals with anti-TGF-beta antibodies by intraperitoneal injection daily on days 0-8 post-tumor cell implantation increased the sensitivity of the EMT-6/Parent tumor to cyclophosphamide (CTX) and cisplatin (CDDP) and markedly increased the sensitivity of the EMT-6/CTX tumor to CTX and the EMT6/CDDP tumor to CDDP, as determined by tumor cell survival assay. Bone marrow granulocyte-macrophage colony-forming units (CFU-GM) survival was determined from these same animals. The increase in the sensitivity in the tumors upon treatment with the anti-TGF-beta antibodies was also observed in increased sensitivity of the bone marrow CFU-GM to CTX and CDDP. Treatment of non-tumor-bearing animals with the anti-TGF-beta regimen did not alter blood ATP or serum glucose level but did decrease serum lactate levels. This treatment also decreased hepatic glutathione, glutathione S-transferase, glutathione reductase, and glutathione peroxidase in non-tumor bearing animals by 40-60% but increased hepatic cytochrome P450 reductase in these normal animals. Animals bearing the EMT-6/CTX and EMT-6/CDDP tumors had higher serum lactate levels than normal or EMT-6/Parent tumor-bearing animals; these were decreased by the anti-TGF-beta regimen. Treatment of animals bearing any of the three tumors with the anti-TGF-beta regimen decreased by 30-50% the activity of hepatic glutathione S-transferase and glutathione peroxidase, and increased by 35-80% the activity of hepatic cytochrome P450 reductase. In conclusion, treatment with transforming growth factor-beta-neutralizing antibodies restored drug sensitivity in the alkylating agent-resistant tumors, altering both the tumor and host metabolic states.

Animals↗

PubMed2002

Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray.

Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the "antioxidant response element" in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 -/-) mice treated with vehicle or sulforaphane (9 micromol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing approximately 6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), gamma-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.

Animals↗

PubMed1988

Glutathione depletion in the lens of galactosemic and diabetic rats.

Depletion of lens glutathione (GSH) occurs quickly and drastically following induction of diabetes or galactosemia in rats as well as in lens culture. The explanation for this dramatic loss of GSH has been investigated by many laboratories but the solution has been elusive. There are several possible causes for the change in the reducing power of the lens under hyperglycemia. (a) The enzyme glutathione reductase which reduces oxidized glutathione to GSH is inhibited. (b) The cofactor NADPH which both the aldose reductase of polyol pathway and glutathione reductase require becomes depleted under hyperglycemia to the point that there is an insufficient amount for glutathione reduction. (c) Membrane permeability is increased, due to osmotic-induced lens hydration. We explored all the above possibilities in the mechanism of GSH depletion and studied the effect of aldose reductase inhibitor (ARI) on osmotic change. We found that under hyperglycemic condition, there was no change in the enzyme glutathione reductase activity. There was an initial drop in NADPH level but there was sufficient remaining for glutathione reductase use. Both NADPH and glutathione depletion could be prevented completely by ARI. In addition, ARI could also prevent any hyperglycemic-induced abnormal transport and leakage of amino acids. We have therefore concluded that only the decreased membrane transport of amino acids which are needed for glutathione biosynthesis and the simultaneous loss of GSH through leaky membrane as initiated by the polyol pathway can be responsible for the drastic GSH depletion.

Aldehyde Reductase↗