Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In rat chemical hepatocarcinogenesis models, the hepatocytes in the preneoplastic/neoplastic nodules characteristically demonstrate common biochemical changes including significant and often marked elevation in the cellular glutathione (GSH) content and in the activities of the enzymes gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase (GST). Such consistent and concomitant biochemical changes may signify a common regulatory mechanism in the expression of these enzymes. We have utilized a panel of clonally derived rat liver epithelial cell lines that express varying activities of GGT to study the quantitative correlation between these three cellular components of the phase II drug metabolizing enzyme system. The results indicate that in confluent cultures, cells with high GGT activities have significantly higher cellular GSH content, and a linear correlation exists between the glutathione content and the logarithm of the GGT activity. In contrast, the basal activities of GST and GGT were not coordinately regulated. However, most of the chemical carcinogen-treated cell lines, regardless of their GGT activity, expressed higher GST activity than the normal parental rat liver epithelial cells. The basal expressions of both the Yb and Yp subunits of GST were also not correlated with the relative expression of GGT. Since GGT may play an important role in supplying the cells with the basic constituents for the synthesis of GSH and since GSH is an important cellular molecule in the protection of cells from toxic electrophiles, enhancement of GGT activity in preneoplastic/neoplastic nodules of chemical carcinogen-treated rats may represent a necessary biochemical adaptation for the induction of the "resistant" phenotype of these hepatocytes.
Mol Carcinog 1989
PMID:Glutathione and glutathione S-transferases in clones of cultured rat liver epithelial cells that express varying activity of gamma-glutamyl transpeptidase. 247 28

The gene for the rat GST Ya subunit has been examined in detail as a model for understanding the molecular mechanisms of inducibility by xenobiotics and their tissue-specific regulation. The focus of this article is to describe our current understanding of these mechanisms. The discussion will begin with the classification of the types of inducing agents. These pioneering studies suggested that there were multiple mechanisms for the inducibility of GSTs. In fact, the analysis of GST Ya gene expression has identified two different upstream activating elements and putative protein factors through which different classes of inducers act. Finally, the position-specific and tissue-specific regulation of the GST Ya gene will be discussed.
Mol Toxicol
PMID:Xenobiotic regulation of glutathione S-transferase Ya gene expression. 249 Sep 78

Glutathione peroxidase and glutathione S-transferase both utilize glutathione (GSH) to destroy organic hydroperoxides, and these enzymes are thought to serve an antioxidant function in mammalian cells by catalyzing the destruction of lipid hydroperoxides. Only two groups of procaryotes, the purple bacteria and the cyanobacteria, produce GSH, and we show in the present work that representatives from these two groups (Escherichia coli, Beneckea alginolytica, Rhodospirillum rubrum, Chromatium vinosum, and Anabaena sp. strain 7119) lack significant glutathione peroxidase and glutathione S-transferase activities. This finding, coupled with the general absence of polyunsaturated fatty acids in procaryotes, suggests that GSH-dependent peroxidases evolved in eucaryotes in response to the need to protect against polyunsaturated fatty acid oxidation. A second antioxidant function of GSH is mediated by glutathione thioltransferase, which catalyzes the reduction of various cellular disulfides by GSH. Two of the five GSH-producing bacteria studied (E. coli and B. alginolytica) produced higher levels of glutathione thioltransferase than found in rat liver, whereas the activity was absent in the other three species studied. The halobacteria produce gamma-glutamylcysteine rather than GSH, and assays for gamma-glutamylcysteine-dependent enzymes demonstrated an absence of peroxidase and S-transferase activities but the presence of significant thioltransferase activity. Based upon these results it appears that GSH and gamma-glutamylcysteine do not function in bacteria as antioxidants directed against organic hydroperoxides but do play a significant, although not universal, role in maintaining disulfides in a reduced state.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1989 Nov
PMID:Evolution of antioxidant mechanisms: thiol-dependent peroxidases and thioltransferase among procaryotes. 251 92

Whey acidic protein (WAP) has been measured by radioimmunoassay in the mammary gland of rats over pregnancy and lactation, and in mammary gland explants incubated with glucocorticoid or progestin in vitro. The radioimmunoassay used a novel fusion protein, glutathione transferase-WAP (GT-WAP), which can be iodinated with ease, unlike the native protein. Mammary gland WAP levels were low (less than 100 ng/mg tissue) until 2-3 days before parturition, but rose to 3 micrograms/mg tissue at day 21 of pregnancy. Immediately after parturition WAP content decreased to 1 micrograms/mg tissue, and then increased to greater than 5 micrograms/mg tissue during mid-lactation. Similarly, alpha-lactalbumin content was low throughout pregnancy (less than 10 ng/mg tissue) until day 20. Thereafter, values rose on the last day of pregnancy and the first day of lactation, fell briefly in early lactation like WAP, and rose to plateau levels by day 11 of lactation. In vitro explants prepared from mid-pregnant rats (day 14) synthesized WAP in the presence of insulin and prolactin. The synthetic glucocorticoid RU26988 (11 beta,17 beta-hydroxy-17 alpha-(1-propynyl)-androsta-1,4,6-trien-3-one) progressively increased WAP production to a maximum of greater than 10-fold basal (in the presence of insulin and prolactin) at 300 nM, in contrast with alpha-lactalbumin which showed a biphasic dose-response curve in explants from mid-pregnant rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1989 Oct
PMID:Mammary gland whey acidic protein: ontogeny and changing patterns of steroid sensitivity. 269 56

Increased expression of the glutathione S-transferase (GST; E.C.2.5.1.18) pi class isozyme is associated with both malignant transformation and drug resistance, as well as with decreased estrogen receptor content in breast cancer. In order to further characterize the role of this enzyme in drug resistance, we cloned the cDNA encoding the human isozyme GST pi and developed two eukaryotic expression vectors using this cDNA and either the human metallothionein IIa or cytomegalovirus immediate-early promoters. These GST pi expression vectors were cotransfected with pSV2neo into drug-sensitive MCF-7 human breast cancer cells, which have low amounts of GST activity and which do not express GST pi. The transfected cells were selected for G418 resistance and individual clones were screened for GST activity. Three clones that demonstrated increased GST activity were selected for further study. Immunoprecipitation studies demonstrated that the increase in GST activity in these clones was due to expression of GST pi. Although the total GST activity of the positive clones was increased as much as 15-fold over that in wild-type MCF-7 cells, there was no change in glutathione peroxidase activity, as measured using cumene hydroperoxide as a substrate. Immunoblot studies revealed that the increased GST enzyme produced in the transfected cells was identical in size to endogenous GST pi. Southern blot analysis demonstrated the incorporation of the GST pi expression vector into the genome of the positive clones and Northern blot analysis showed that the transfected genes made a hybrid GST pi RNA that was slightly larger than the endogenous GST pi RNA. Primer extension studies demonstrated that this increase in length corresponded to the added length of the 5' leader sequence of the expression vector. The effect of increased GST pi activity on the sensitivity of the transfected clones to several cytotoxic agents was assessed by colony-forming assay. The transfected clones were slightly more resistant (1.3-4.1-fold) to benzo(a)pyrene and its toxic metabolite benzo(a)pyrene-(anti)-7,8-dihydrodiol-9,10-epoxide, as well as to ethacrynic acid (3.1-to 4.4-fold). Although increased GST pi expression is found in MCF-7 cells selected for doxorubicin resistance, the transfected clones were not consistently more resistant to doxorubicin than control cells. In addition, the transfected cells were not resistant to either melphalan or (cis)-platinum, even though conjugation with glutathione is known to play a role in the detoxification of both of these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1989 Jul
PMID:Elevation of pi class glutathione S-transferase activity in human breast cancer cells by transfection of the GST pi gene and its effect on sensitivity to toxins. 274 27

Rodent milk consists mainly of caseins and whey proteins. A major component of the latter group is the whey acidic proteins (WAP) the gene for which has been cloned recently and shown to contain several potential glucocorticoid receptor binding sites. Studies on the regulation of this gene by glucocorticoids would be greatly enhanced by the availability of a radioimmunoassay for WAP. Rat milk was obtained from lactating Sprague-Dawley rats and the WAP purified to homogeneity by ammonium sulphate fractionation, gel filtration and ion exchange chromatography. Rabbit polyclonal antibodies were raised against the purified WAP and used to probe a Western blot of whey proteins. The major band recognized by the antibody corresponded in molecular weight to purified WAP. Problems associated with radiolabelling the tyrosine-free WAP molecule necessitated the fusion of a tyrosine containing protein with the rat milk protein. A rat WAP cDNA clone was ligated to the glutathione transferase gene, the fusion protein expressed in Escherichia coli and purified by a one-step procedure on a glutathione affinity column. Purified WAP readily displaced the radiolabelled recombinant tracer in a radioimmunoassay.
Mol Cell Endocrinol 1989 May
PMID:Generation of polyclonal antibodies against purified rat whey acidic proteins and the synthesis of a tracer fusion protein suitable for use in radioimmunoassays. 275 23

Single crystals of human GST2, a class alpha glutathione transferase have been grown in polyethylene glycol 2000 by the hanging-drop vapour diffusion method. The crystals belong to space group C2 and have cell dimensions a = 100.8 A, b = 95.4 A, c = 105.2 A and beta = 92.4 degrees. The X-ray diffraction pattern extends to better than 3 A resolution.
J Mol Biol 1989 Jul 20
PMID:Crystallization of GST2, a human class alpha glutathione transferase. 276 66

The gene expression of liver major gap junction (GJ) protein was studied in rats systemically administered phenobarbital, a rat liver tumor promoter. Using a GJ protein cDNA and northern blot analysis, the level of GJ protein mRNA in liver was observed to be markedly reduced at 4 and 11 wk of phenobarbital exposure (0.1% in drinking water). However, the level of GJ protein mRNA was not altered in kidney at 11 wk of exposure. In liver, phenobarbital did not induce expression of the neoplasm-associated marker genes glutathione S-transferase (placental form) and gamma-glutamyltranspeptidase, while in kidney the observed expression of these genes was not changed. These in vivo results indicate that phenobarbital reduces GJ protein gene expression specifically in rat liver without altering expression of genes often altered during liver carcinogenesis, and they support assigning a role for the impairment of gap junctional intercellular communication in phenobarbital-mediated liver tumor promotion.
Mol Carcinog 1988
PMID:Phenobarbital specifically reduces gap junction protein mRNA level in rat liver. 285 4

Immunohistochemical investigation of focal proliferative and neoplastic Syrian hamster pancreatic lesions induced by propylnitrosamine administration revealed a distinct pattern of expression of different molecular forms of glutathione S-transferase (GST) during neoplastic development. Initial increase in levels of GST placental (P) and B forms in early ductal/ductular proliferations and atypical (dysplastic) lesions was followed by a drop in the latter during transition to carcinoma. Unequivocal acinar cells observed within so-called 'pseudoductules' did not share the altered phenotype evident in ductular elements, suggesting their non-involvement in the generation of early lesions. However, the fact that component cells were occasionally of abnormal morphology did not allow the exclusion of acinar cell participation in histogenesis. Elevation of GST-A and C forms was limited to stromal elements surrounding the epithelial lesions and since they were associated with benign, cystic as well as atypical lesions and a similar increase was observed after common duct ligation, they appeared to be non-specific. The results indicated independent control of expression of individual GST forms and suggest that biochemical similarities exist between early, putative preneoplastic lesions induced by propylnitrosamines in the hamster lung, liver (both hepatocellular and intrahepatic bile duct) and pancreas.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Immunohistochemically demonstrated increase in glutathione S-transferase species in propylnitrosamine-induced focal proliferative and neoplastic Syrian hamster pancreatic lesions. 288 70

Focal proliferative and neoplastic lung lesions induced in Syrian hamsters by dihydroxy-di-n-propylnitrosamine (DHPN) were investigated using a combined histochemical, autoradiographic and electron microscopic approach. Expression of elevated glucose-6-phosphate dehydrogenase (G6PD) and gammaglutamyl-transpeptidase (GGT) activities and levels of immunohistochemically demonstrable glutathione S-transferase placental form (GST-P) were evident in epithelial cells of focal proliferative populations and bronchioloalveolar neoplasms. Binding for the GST-C form, normally only weak, became very pronounced in the stromal elements of DHPN-induced lesions. Increased labelling with tritiated thymidine was associated with increase in morphological atypia within the tumours. Although the enzyme phenotype findings were equivocal the presence of lamellar bodies in some cells of focal proliferative and neoplastic lesions suggested an origin from alveolar type II cells. The present results regarding changed enzyme phenotype in lung lesions suggest important similarities at the biochemical level for the process of neoplasia in the different target organs of DHPN in the hamster and indicate that GST-P may be a useful 'marker' for lung neoplasia.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Altered enzyme expression in propylnitrosamine-induced Syrian hamster lung lesions. 288 90


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