Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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1. Radiotherapy has attracted increasing interest in recent years. It is known that ionizing radiation induces oxygen radical injury, whereas oxidative stress by the radiation can cause cellular responses to defense cellular injury. In this study, the metabolism of antioxidants in response to ionizing radiation to the brain was studied in the brain using experimental rabbits. 2. Ionizing radiation to the hemicerebrum caused an increase in the levels of glutathione (GSH) and the activity of a GSH synthesizing enzyme, gamma-glutamylcysteine synthetase (gamma-GCS), and Cu,Zn-superoxide dismutase (Cu,Zn-SOD). Ionizing radiation also induced DNA-damage estimated by the formation of 8-hydroxydeoxyguanosine. These changes were dependent on the radiation dose. 3. Previous intrathecal-administration of buthionine sulfoximine (100 microM), a specific inhibitor of gamma-GCS, increased DNA damage by radiation in the radiated hemicerebrum. That of S-methyl GSH, on the other hand, resulted in a significant reduction of DNA damage by radiation. 4. These results suggest that synthesis of GSH and Cu,Zn-SOD is responsive to ionizing radiation and this induction of antioxidants may play a role in reducing tissue damage in radiotherapy.
Cell Mol Neurobiol 1998 Jun
PMID:Protective role of glutathione synthesis on radiation-induced DNA damage in rabbit brain. 959 May 60

In roots of Brassica juncea L. cadmium (Cd) exposure (25 microM) induces a massive formation of phytochelatins (PCs), which is accompanied by an only moderate decrease (-20%) of the putative PC precursor glutathione (GSH). As PC formation in roots could be the result of local GSH de novo synthesis and/or depend on GSH import from the shoot, we have analyzed the expression of the enzymes involved in GSH synthesis in the root, namely OAS(thiol)lyase (OAS-TL; catalysing the last step in Cys biosynthesis), gamma-glutamylcysteine synthetase (gamma-ECS), and glutathione synthetase (GSHS). cDNA clones were isolated from a cDNA library prepared from heavy metal exposed roots. Protein sequences from cDNA clones encoding OAS-TL, gamma-ECS, and GSHS, all exhibited putative mitochondrial targeting sequences, however, for OAS-TL also two putative cytosolic isoforms were isolated. Furthermore, we have cloned several metallothionein cDNAs of the MT2 group. Northern blot analysis with coding region probes revealed that in roots of Cd-exposed plants transcript amounts for OAS-TL and GSHS were only moderately increased, whereas gamma-ECS mRNA showed a stronger increase. Expression analysis with 3'-UTR probes indicated that among the putative mitochondrial OAS-TL, gamma-ECS and GSHS isoforms only gamma-ECS was up-regulated in response to Cd exposure. Conversely, transcripts for MT2 appeared to be slightly reduced. The results indicate that in roots Cd-induced PC synthesis correlates with a moderate increase of expression of genes involved in GSH synthesis, the change for gamma-ECS being most pronounced.
Plant Mol Biol 1998 May
PMID:cDNA cloning and expression analysis of genes encoding GSH synthesis in roots of the heavy-metal accumulator Brassica juncea L.: evidence for Cd-induction of a putative mitochondrial gamma-glutamylcysteine synthetase isoform. 962 Feb 67

Elevation of activity and mRNA level of a cytosolic aldehyde dehydrogenase-1 (ALDH1), which oxidizes aldophosphamide, was previously observed in a cyclophosphamide-resistant murine leukemia cell line. However, changes in other enzyme(s) which may detoxify the drug or produce anti-alkylating agent(s), have not been examined. The human leukemia cell line, K562, was made 30-fold resistant against 4-hydroperoxycyclophosphamide (4HC) by exposing the cells to increasing concentrations of the drug. Resistance against cisplatin was also increased by about 3-fold. Activities of glucose-6-phosphate dehydrogenase (G6PD) and ALDH1 were elevated more than 7-fold in the resistant cells. The mRNA level of the two enzymes was also proportionally elevated. The concentration of reduced glutathione (GSH) was higher in the resistant cells (i.e., 21.1 versus 4.68 nmole per 10(6) cells), while activities of gamma-glutamylcysteine synthetase and glutathione synthetase, and the expressions of other human ALDH genes were not increased in the resistant cells. These findings suggest that the acquired resistance against 4HC is a consequence of transcriptional activation of two genes, i.e., one encoding the G6PD, a major enzyme regenerating anti-alkylating GSH, and the other encoding ALDH1, which has a high activity for oxidation of aldophosphamide derived from 4HC.
Blood Cells Mol Dis 1998 Jun
PMID:Enhanced expressions of glucose-6-phosphate dehydrogenase and cytosolic aldehyde dehydrogenase and elevation of reduced glutathione level in cyclophosphamide-resistant human leukemia cells. 971

Homeostatic mechanisms for the maintenance of glutathione (GSH) are fundamental in the provision of a cellular defense against electrophilic/oxidant challenges. Cyclopentenone prostaglandins (CP-PGs) are powerful antiproliferative endogenous substances that may act as electrophilic regulating compounds, by virtue of the presence of an alpha,beta-unsaturated carbonyl group in the cyclopentane ring. Nevertheless, differential resistance to CP-PG cytotoxic/cytostatic effect has been reported in different cell types. It is reported that the activity/expression of gamma-glutamylcysteine synthetase (gamma-GCS, the rate-limiting enzyme in GSH biosynthesis) can be inducibly activated by electrophiles, including CP-PGs. The response of the human cancer strains HEp-2 (larynx carcinoma) and HL-60 (promyelocytic leukemia) cells to treatment with the CP-PG PGA1 in culture was investigated by evaluating the time-course of GSH synthesis and activity of enzymes of GSH metabolism, other than gamma-GCS, after PGA1 addition. HEp-2 cells, being more resistant to PGA1 cytotoxic and cytostatic effects, have basal GSH levels that were 2.4-fold higher than that of HL-60 cells. The activities of GSH S-transferase (GST), glutathione reductase (GSRd) and glutathione peroxidase (GSPx) are constitutively higher in HL-60 cells than in HEp-2 cells (respectively, 17.0-, 28.5- and 12.3-fold). When challenged with PGA1, both cell types exhibited a dose-dependent rise in GSH content that was maximal 18 h after PGA1 addition and was preceded by a rise in GST and GSRd activities in both cell types (at 12 h). GSPx activity increased only in HEp-2 (PGA1 evoked a 93.4%-inhibition in HL-60 cells). Moreover only HEp-2 cells exhibited early capacity to enhance GSH content (1-2 h just after PGA1 addition). These results and earlier data showing that leukemia cells are sensitive to CP-PG treatment suggest that deficiencies in GSH metabolism may be strategically in therapeutic approaches to the treatment of human leukemias.
Biochem Mol Biol Int 1998 Sep
PMID:Effects of the antiproliferative cyclopentenone prostaglandin A1 on glutathione metabolism in human cancer cells in culture. 976 23

The putative gene for gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione biosynthesis, has been characterized both in Plasmodium berghei and Plasmodium falciparum. Protein sequence comparison between these two species reveals large conserved regions sharing more than 80% similarity, separated by less conserved portions. When the comparison is extended to known gamma-glutamylcysteine synthetases from other eukaryotes, a number of high similarity blocks are observed which may help in identifying sequence essential for protein function.
Mol Biochem Parasitol 1999 Mar 15
PMID:The putative gene for the first enzyme of glutathione biosynthesis in Plasmodium berghei and Plasmodium falciparum. 1021 22

The mechanisms of the cellular effects and DNA damage caused by asbestos fibers in human mesothelial cells are not well understood. We exposed transformed human pleural mesothelial cells to 1-4 microg/cm2 crocidolite and to 10-100 ng/ml tumor necrosis factor alpha for up to 48 hr and studied the induction of DNA damage using the Comet assay. As a positive control, 100 microM H2O2 was used. The DNA single strand breaks were assessed as the mean tail moments and as distributions of the tail DNA in the cell. The Comet assay showed significant but reversible increases in the mean tail moments, but not in the distribution of Comet tails in the histograms in cells exposed to 1 microg/cm2 crocidolite for 6 hr. At higher concentrations of asbestos fibers all the indices in the Comet assay showed significant and irreversible change. All the doses of TNF-alpha caused marginal increase in the mean tail moments. The mean tail moments were highest in the cells with concurrent treatment to TNF-alpha and crocidolite. In the cells pretreated with inhibitors of antioxidant enzymes (aminotriazole for catalase and buthionine sulfoximine for gamma-glutamylcysteine synthetase) asbestos fibers slightly increased oxidant-related fluorescence of dichlorofluorescein (DCFH) but did not cause any further increases in the mean tail moments. This study shows that asbestos fibers cause DNA single strand breaks in human mesothelial cells. Since the inhibition of antioxidant enzymes did not have an effect on the DNA damage caused by the fibers, other mechanisms than free radicals seem to be involved in the induction of DNA damage by mineral fibers.
Environ Mol Mutagen 1999
PMID:DNA single strand breaks induced by asbestos fibers in human pleural mesothelial cells in vitro. 1021 69

The heavy-metal accumulator Brassica juncea L. is a high-biomass crop able to extract heavy-metal ions from the soil, a substantial part being translocated from root to shoot. Previous work has shown that Cd accumulation is accompanied by massive formation of phytochelatins (PCs). Rapid de novo synthesis of PCs in roots and leaves requires an increased synthesis of the tripeptide glutathione (GSH), which in turn depends on increased sulfur assimilation. Therefore. we have cloned cDNAs for three enzymes involved in sulfur assimilation, i.e. a putative low-affinity sulfate transporter (LAST) and two isoforms each for ATP sulfurylase (ATPS) and APS reductase (APSR). As degradation of glucosinolates might provide an additional sulfur source under stress, we also cloned a myrosinase (MYR). RNA blot analysis of transcript amounts indicated that upon Cd exposure (25 microM) the expression of ATPS and APSR in roots and leaves of 6-week-old Brassica juncea plants was strongly increased, whereas the expression of MYR was unaffected. LAST transcripts were significantly reduced in the root but remained unchanged in the leaves. Concomitant with Cd induction of ATPS and APSR mRNAs, cysteine concentrations in roots and leaves increased by 81% and 25%, respectively, whereas GSH concentrations decreased in roots and leaves by 39% and 48%, respectively. In agreement with our previous report on Cd induction of gamma-glutamylcysteine synthetase in B. juncea, the results indicate coordinate changes of expression for several sulfur assimilation enzymes in response to an increased demand for cysteine during PC synthesis.
Plant Mol Biol 1999 Mar
PMID:Cloning sulfur assimilation genes of Brassica juncea L.: cadmium differentially affects the expression of a putative low-affinity sulfate transporter and isoforms of ATP sulfurylase and APS reductase. 1035 97

The mRNA expression of five enzymes: catalase, Cu-Zn-superoxide dismutase (Cu-Zn-SOD), Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPX), and gamma-glutamylcysteine synthetase (GCS) each involved in protection against free radicals was studied in human and mouse oocytes. In the mouse, oocytes were collected at different stages of maturation in order to determine the storage of these transcripts. For the human, germinal vesicle (GV) oocytes harvested during intracytoplasmic sperm injection (ICSI) procedures and failed fertilized metaphase II (MII) oocytes were analysed. Human and mouse were compared in order to determine whether the differential developmental capacity of mouse and human preimplantation embryos in culture could be explained by the variations in the patterns of expression for these enzymes. mRNA expression for these enzymes was examined using reverse transcription-polymerase chain reaction (RT-PCR). In the mouse, all transcripts (except for catalase) were detected, whatever the maturation stage. No qualitative differences were detected between GV and MII oocytes. In human, all the enzymes (except for catalase) were expressed in MII oocytes and Cu-Zn-SOD was particularly highly expressed. Transcripts corresponding to GPX and Mn-SOD were not detected at GV stage but only at MII stage, suggesting that storage could occur between GV and MII stages. However, using 3' end-specific primers for GPX and Mn-SOD, instead of the oligo(dT)(12-18) primer, for the reverse transcription reaction, the transcripts for these antioxidants enzymes have been detected in human oocytes at the GV stage. This suggests the presence of maturation-specific polyadenylation of these transcripts. These enzymes can be considered as markers of cytoplasmic maturation.
Mol Hum Reprod 1999 Aug
PMID:Expression of genes encoding antioxidant enzymes in human and mouse oocytes during the final stages of maturation. 1042 98

The presence of iron in brain tissue in increased concentrations in Parkinson's disease cases, where it might be responsible for oxidative stress, and the parallel observation that the iron transporter lactoferrin (Lf) was present in increased amounts in surviving neurons, led us to study the synthesis of Lf in a mouse model of Parkinson's disease. In this context, the origin and expression of brain Lf in normal, aged and MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine)-treated mice were investigated. Lf immunostaining was observed mainly on microvessels in the cerebral cortex of the adult mice and to a greater extent in older mice. Lf immunoreactivity was also present in the hippocampus only in the aged mouse brains, associated with structures which seemed to be pyramidal neurons and fibers. After RT-PCR (polymerase chain reaction), Lf transcripts were found in mouse brain tissue whatever the age of the animals studied but the level of their expression was very low. No up-regulation of Lf was detectable during aging. Lf distribution and expression in the MPTP-induced Parkinsonian mouse model were also investigated. A marked depletion of dopamine (DA) occurred in the high dose MPTP-treated mice. The level of Lf expression was found to be markedly increased in the same animals and this up-regulation occurred on the first day after MPTP administration. When the brain was stressed by the neurotoxin MPTP, Lf expression increased in line with antioxidant enzymes such as catalase and gamma-glutamylcysteine synthetase, which may permit the protection of brain tissue from oxidative damage induced by the drug.
Brain Res Mol Brain Res 1999 Oct 01
PMID:Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. 1052 77

To test the genetic capacity of the perinatal lung to respond to O(2) shifts that coincide with the first respiratory movements, rat fetal alveolar type II (fATII) epithelial cells were cultured at fetal distal lung PO(2) (23 Torr) and then exposed to postnatal (23 --> 76 Torr; mild hyperoxic shift), moderate (23 --> 152 Torr; moderate hyperoxic shift), or severe (23 --> 722 Torr; severe hyperoxic shift) oxygenation. Nuclear abundance and consensus binding characteristics of hypoxia-inducible factor (HIF)-1alpha and nuclear factor (NF)-kappaB (Rel A/p65) plus glutathione biosynthetic capacity were determined. Maximal HIF-1alpha activation at 23 Torr was sustained over the postnatal shift in (Delta) PO(2) and was elevated in vivo throughout late gestation. NF-kappaB was activated by the acute postnatal DeltaPO(2) in fATII cells, becoming maximal with moderate and severe oxygenation in vitro and within 6 h of birth in vivo, declining thereafter. fATII cell and whole lung glutathione and GSH-to-GSSG ratio increased fourfold with a postnatal DeltaPO(2) and were matched by threefold activity increases in gamma-glutamylcysteine synthetase and glutathione synthase. GSH concentration depletion by L-buthionine-(S, R)-sulfoximine abrogated both HIF-1alpha and NF-kappaB activation, with HIF-1alpha showing a heightened sensitivity to GSH concentration. We conclude that O(2)-linked genetic regulation in perinatal lung epithelium is responsive to developmental changes in glutathione biosynthetic capacity.
Am J Physiol Lung Cell Mol Physiol 2000 Mar
PMID:O(2)-evoked regulation of HIF-1alpha and NF-kappaB in perinatal lung epithelium requires glutathione biosynthesis. 1071 May 21


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