Identification of a New Glutathione S-Transferase in Human Liver.

Warholm, Margareta; Guthenberg, Claes; Mannervik, Bengt; C, von Bahr; Glaumann, Hans

doi:10.3891/acta.chem.scand.34b-0607

Cited by 62 publications

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“…Each liver contained two major forms of glutathione transferase that focused at a basic and an acid pH, respectively. Such an isoenzyme pattern of glutathione transferase is in accordance with our previous findings [Warholm et al, 1981b], In addition to the major basic and acidic isoenzymes, the activity profiles ob tained in several of the livers suggested the…”

Section: Assayssupporting

confidence: 77%

“…Multiple forms of the enzyme have been resolved and it appears that each class may contain several members of transferase. In human adult liver, the main part of the activity is contained in the basic and, in cer tain individuals, the near-neutral fraction [Kamisaka et al, 1975;Warholm et al, 1980Warholm et al, , 1981bWarholm et al, , 1983Soma étal., 1986;Stockman et al, 1985;Vander Jagt et al, 1985]. In contrast, the human fetal liver contains a major acidic transferase in addition to a ma jor basic form [Warholm et al, 1981b;Guthenberg et al, 1986;Pacifici et al, 1986], These two fetal forms have recently been purified and characterized , Studies using styrene oxide as substrate revealed that the enzyme activity in the cyto sol displayed non-Michaelian kinetics when the concentration of glutathione was varied at a fixed concentration of the electrophilic substrate , The interpre tation of these results was difficult, since it was unknown whether the 'biphasic' kinetics were due to the catalytic properties of a sin gle enzyme molecule or to the sum of the activities of different isoenzymes.…”

Section: Introductionmentioning

confidence: 99%

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Conjugation of Styrene Oxide by the Basic and Acidic Forms of Glutathione Transferase in the Human Fetal Liver

Pacifici

Guthenberg²,

Warholm³

et al. 1988

Dev Pharmacol Ther

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Two forms of glutathione transferase were isolated by means of isoelectric focusing of human fetal liver cytosol preparations. The enzyme activity was measured with l-chloro-2,4-dinitrobenzene as the electrophilic substrate. One peak focused at pH 9-10 (basic form) and the other at pH 4-5 (acidic form). The basic and the acidic forms are representatives of glutathione transferase classes a and n, respectively. These classes constitute two of the three classes defined for cytosolic forms of the enzyme in several mammalian species [Mannervik et al., Proc. natn. Acad. Sci. USA 82: 7202-7206, 1985], Only the basic fraction isolated from human fetal liver catalyzed the conjugation of styrene oxide with glutathione at a significant rate. The kinetics of this form were studied keeping the concentration of styrene oxide constant (6 mM) and varying the glutathione concentration from 0.05 to 25 mM. The enzyme activity displayed non-Michaelis-Menten kinetics. The basic and acidic forms of glutathione transferase from a fetal liver were purified to homogeneity. Both purified forms catalyzed the conjugation of glutathione with styrene oxide. The kinetics were studied at varying glutathione concentrations and for both forms, it was found to be of a non-Michaelis-Menten type. The results are consistent with previous findings in the cytosolic fraction [Pacifici et al., Biochem. Pharmac. 30: 3367-3371, 1981] and show that the non- Michaelian kinetics observed with glutathione in human fetal liver cytosol are reflections of the intrinsic properties of the basic as well as the acid form of this enzyme and not primarily depending on the simultaneous catalytic action of the two forms.

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Section: Assayssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Conjugation of Styrene Oxide by the Basic and Acidic Forms of Glutathione Transferase in the Human Fetal Liver

Pacifici

Guthenberg²,

Warholm³

et al. 1988

Dev Pharmacol Ther

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“…Demonstration that variation occurs in GST forms present in human tissue extracts and red blood cells of different individuals was initially achieved using starch-gel electrophoresis and isoelectric focusing [58][59][60][61]. Although of great value, these physicochemical approaches were limited to analysis of those class Alpha, Mu and Pi isoenzymes that are particularly active with CDNB.…”

Section: Polymorphisms In Gst Genesmentioning

confidence: 99%

Glutathione S-Transferase Polymorphisms and Their Biological Consequences

2000

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Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1*0, GSTT1*0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility.

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“…In human liver, the transferases have been di vided into three groups: basic, neutral and acidic. Five basic transferases have been identified (a, p, y, 8, e) which were consid ered charge isomers since they are homodi mers of a single subunit (Mr 25,000) [4], A distinct subunit (Mr 26,300) has been de scribed for the neutral form (transferase p) [5]. This form, however, is absent in nearly half of the livers which have been examined.…”

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confidence: 99%

“…This form, however, is absent in nearly half of the livers which have been examined. The acidic forms have been noted to be present in only trace amounts in human liver [5][6][7], The acidic forms (to and vji) from liver [8] have been noted to be immunochemically similar to erythrocyte enzyme [9] (transferase p) or placental (transferases it) enzymes [10], Immunochemical and electrophoretic studies have supported the view that the bas ic, neutral and acidic transferases are dis tinct gene products [11,12]. Recently our preliminary results [Hepatology 4: 1082[Hepatology 4: , 1984, abstract] along with several other labo ratories [13,14] have suggested that the basic transferases from human liver are com binations of two distinct subunits.…”

mentioning

confidence: 99%

Subunit Heterogeneity of Cationic Human Hepatic Glutathione S-Transferases

et al. 1987

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We have purified the major reduced glutathione (GSH) S-transferases from 3 apparently normal human livers: two obtained at surgery and one at autopsy. Purification was by sequential gel filtration, GSH-affinity chromatography, and chromatofocusing. All three livers exhibited the same two major transferase peaks from chromatofocusing at pH 9.0 and 8.7 (designated C1 and C2, respectively) and several (2–4) minor peaks. Another major form (designated A1) from two livers eluted from chromatofocusing at pH 5.4, whereas the major form from the third liver (designated N1) eluted near neutral (pH 6.8). The transferase from erythrocytes eluted at pH 4.6. Isoelectric focusing revealed that the true pi of Al was pH 7.1 indicating that Cl, C2 and Al are all cationic. In sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, Cl, C2 and Al exhibited the same single subunit (25,000) whereas Nl was different (26,000). The erythrocyte enzyme had a smaller subunit (23,500). Urea/SDS-polyacrylamide gel electrophoresis resolved the apparent single subunit of Al, Cl and C2 into two distinct subunits. Cl from all 3 livers was a homodimer of the faster migrating subunit (designated subunit I); C2 was a heterodimer (designated I–II); and A1 was a homodimer of the slower migrating subunit (designated subunit II). Hybridization experiments demonstrated that by mixing C1 and A1 we could produce C2 whereas dissociation and reassociation of the subunits of C2 generated C1 and A1 as well as C2. Rabbit antiserum to C1 recognized C1 and C2, but not A1. Thus, the cationic human hepatic transferases are dimers of two distinct subunits.

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Identification of a New Glutathione S-Transferase in Human Liver.

Cited by 62 publications

References 0 publications

Conjugation of Styrene Oxide by the Basic and Acidic Forms of Glutathione Transferase in the Human Fetal Liver

Conjugation of Styrene Oxide by the Basic and Acidic Forms of Glutathione Transferase in the Human Fetal Liver

Glutathione S-Transferase Polymorphisms and Their Biological Consequences

Subunit Heterogeneity of Cationic Human Hepatic Glutathione S-Transferases

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