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PubMed2000

Purification and characterization of rat testicular glutathione S-transferases: role in the synthesis of eicosanoids.

AIM: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identification of various subunits and their role in eicosanoid biosynthesis. METHODS: Purification of rat testicular GSTs by affinity chromatography, employing S-hexylglutathione-linked epoxy-activated Sepharose 6B column and separation of individual subunits by reverse phase-high pressure liquid chromatography (RP-HPLC). Characterization of affinity purified GSTs by Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis. The role of testicular GSTs in eicosanoid biosynthesis was determine by incubating GSTs with 5, 6-Leukotriene A4Me (LTA4Me) and prostaglandin H2(PGH2) and analyzing the products formed on HPLC/TLC. RESULTS: The present study reveals that majority of rat testicular GSTs are of Yb size (60%) with molecular weight of 27 kDa. The most predominant subunits, however, are GST Yn2(27%), followed by GST Yc(24%) and GST Yn1(20%). These testicular GSTs showed very high Leukotriene C4 (LTC4) synthase activity with 5, 6-Leukotriene A4Me (LTA4Me) as the substrate and prostaglandin D (PGD) synthase activity with prostaglandin H2(PGH2) as the substrate. CONCLUSION: Majority of rat testicular GSTs are Yb sized and are involved in the synthesis of eicosanoids like LTC4 and PGD2.

Androgens↗
PubMed1986

Expression of glutathione S-transferases in rat brains.

The tissue-specific expression of glutathione S-transferases (GSTs) in rat brains has been studied by protein purification, in vitro translation of brain poly(A) RNAs, and RNA blot hybridization with cDNA clones of the Ya, Yb, and Yc subunit of rat liver GSTs. Four classes of GST subunits are expressed in rat brains at Mr 28,000 (Yc), Mr 27,000 (Yb), Mr 26,300, and Mr 25,000. The Mr 26,3000 species, or Y beta, has an electrophoretic mobility between that of Ya and Yb, similar to the liver Yn subunit(s) reported by Hayes (Hayes, J. D. (1984) Biochem. J. 224, 839-852). RNA blot hybridization of brain poly(A) RNAs with a liver Yb cDNA probe revealed two RNA species of approximately 1300 and approximately 1100 nucleotides. The band at approximately 1300 nucleotides was absent in liver poly(A) RNAs. The Mr 25,000 species, or Y delta, can be immunoprecipitated by antisera against rat heart and rat testis GSTs, but not by antiserum against rat liver GSTs. Therefore, the Y delta subunit may be related to the "Mr 22,000" subunit reported by Tu et al. (Tu, C.-P.D., Weiss, M.J., Li, N., and Reddy, C. C. (1983) J. Biol. Chem. 258, 4659-4662). The abundant liver GST subunits, Ya, are not expressed in rat brains as demonstrated by electrophoresis of purified brain GSTs and a lack of isomerase activity toward the Ya-specific substrate, delta 5-androstene-3,17-dione. This is apparently because of the absence of Ya mRNA expression prior to RNA processing. The data on the preferential expression of Yc subunits in rat brains, together with the differential phenobarbital inducibility of the Ya subunit(s) in rat liver reported by Pickett et al. (Pickett, C. B., Donohue, A. M., Lu, A. Y. H., and Hales, B. F. (1982) Arch. Biochem. Biophys. 215, 539-543), suggest that the Ya and Yc genes for rat GSTs are two functionally distinct gene families even though they share 68% DNA sequence homology. The expression of multiple GSTs in rat brains suggests that GSTs may be involved in physiological processes other than xenobiotics metabolism.

Animals↗
PubMed1996

Cellular localization of glutathione S-transferases in retinas of control and lead-treated rats.

PURPOSE: The glutathione S-transferases (GSTs) constitute a family of cytosolic isoenzymes that are involved in the detoxication of electrophilic xenobiotics. The purpose of this investigation was to determine the concentration and cellular distribution of the various classes of cytosolic GSTs in the retina of control and triethyl lead-treated rats and thereby reveal mechanisms by which the cells are protected from damage by lead and other toxicants. METHODS: The regional and cellular distribution of cytosolic GSTs in rat retina of control and lead-treated animals was studied by immunohistochemistry. Enzyme activity was determined by a spectrophotometric assay. The GST subunit distribution of the entire retina of control and lead-treated animals was determined and quantified by reverse-phase high-performance liquid chromatography (HPLC). RESULTS: Polyclonal antibodies against mu-class Yb1 and Yb2 GSTs were primarily and strongly reactive with Müller cells and their processes. Anti-Yb1 also reacted with photoreceptor outer segments. Antibodies against two alpha-class GSTs (Ya and Yk) were strongly reactive with Müller cells and their cell processes. Antibodies against Yp and Yc GSTs were reactive with amacrine cells and their processes, and anti-Yp antibodies were reactive against retinal ganglion cells. Treatment of rats with triethyl lead caused diminished reactions of the antibodies against Yb1 and Yp GSTs and increased reactions of anti-Ya with its retinal targets, whereas the total GST activity did not change significantly. CONCLUSIONS: The positive reaction between the amacrine neuronal cells of retina and the anti-Yp and anti-Yc class antisera broadens the class of neurons that contains GST enzymes protective against toxicant insult. It also has been shown that Müller cells are strongly immuno-positive for Yb1 and Yb2 GST. Because these phagocytic cells are in contact with the vitreous fluid and proximate to pigmented epithelial layer of the eye, these GSTs may protect the cells from toxicants accumulated from this fluid.

Animals↗
PubMed1996

Inhibition of rat, mouse, and human glutathione S-transferase by eugenol and its oxidation products.

The irreversible and reversible inhibition of glutathione S-transferases (GSTs) by eugenol was studied in rat, mouse and man. Using liver cytosol of human, rat and mouse, species differences were found in the rate of irreversible inhibition of GSTs by eugenol in the presence of the enzyme tyrosinase. Tyrosinase was used to oxidize eugenol. No inhibition was observed in the absence of tyrosinase. The rate of irreversible inhibition of GSTs was highest in mouse cytosol, and lowest in rat cytosol. In addition, the irreversible inhibition of human and rat GSTs by eugenol was studied using purified isoenzymes of man and rat. The human GST isoenzymes A1-1, M1a-1a and P1-1 and the rat GST isoenzymes 1-1, 2-2, 3-3, 4-4 and 7-7 were irreversibly inhibited by eugenol in the presence of tyrosinase. In this respect human GST P1-1 and rat GST 7-7 were by far the most sensitive enzymes; human GST A2-2 was not inhibited. Indications were found that human GST P1-1 may be inhibited via three mechanisms: in addition to the well documentated nucleophilic addition of quinones and oxidation of cysteine residues, a covalent subunit cross-linking was also observed. The reversible inhibition of human and rat GST by eugenol, eugenol methyl ether, isoeugenol methyl ether, 2-allylphenol and 4-propylphenol was also studied using purified isoenzymes. The reversible inhibition of human and rat GSTs, using 1-chloro-2,4-dinitrobenzene as substrate, was expressed as I25. All compounds caused moderate reversible inhibition (I25 ranged from 0.2 to 5.4 mM for human GSTs and from 0.4 to 4.9 mM for rat GSTs). In rat, eugenol methyl ether was the strongest inhibitor. In human, the overall inhibiting capacities of eugenol, eugenol methyl ether, isoeugenol methyl ether and 4-propyl phenol were more or less similar; 2-allylphenol was the poorest inhibitor.

Allyl Compounds↗
PubMed1992

Primary sequence heterogeneity and tissue expression of glutathione S-transferases of Fasciola hepatica.

Glutathione S-transferases (GSTs) from Fasciola hepatica have been purified by glutathione affinity chromatography. Two closely migrating species of Mr 26,000 and 26,500 were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and several species resolved by two-dimensional gel analysis, indicating substantial heterogeneity among the GSTs. N-terminal amino acid sequencing revealed one core sequence containing three polymorphisms, whereas the sequence of GST peptides implied a minimum of three different GSTs. The amino acid sequence data assigned the F. hepatica GSTs to the mu class of GSTs with high similarities to these proteins in other helminths and mammals. The native GSTs of F. hepatica appeared to behave as dimers as determined by molecular sieving chromatography. The observation that the GSTs of F. hepatica are heterogeneous in sequence and behave as dimers in the native state suggest that these isoenzymes may exhibit considerable functional heterogeneity which may be of importance to the parasite. Immunocytochemical studies suggest that the main source of GST in F. hepatica are the parenchymal cells and peripheral tissues of the parasite. Some extracellular GST is associated with the lamellae of the intestinal epithelium. The identification of an intestinal GST is unique among trematodes studied to date.

Amino Acid Sequence↗
PubMed2005

Glutathione S-transferases activity in patients with colorectal cancer.

OBJECTIVES: The glutathione S-transferases (GSTs) play a critical role in protecting the colorectal mucosa. We investigated the efficacy of using the GSTs activity of plasma as a biomarker of risk for colorectal cancer. METHODS: GSTs activity was measured in the plasma of control individuals (n=39) and in the plasma, tumor tissue and normal tissue adjacent to a tumor of patients with colorectal cancer taken at colonoscopy (n=60). RESULTS: Mean GSTs activity was significantly (P< 0.01) higher in tumors (242+/- 45 nmol/min mg protein) as compared to normal tissues adjacent to a tumor (84+/- 49 nmol/min mg protein). A significant correlation between normal tissues adjacent to a tumor GSTs with those in malignant tissues was observed (r=0.61). Plasma GSTs activity was significantly (P<0.0001) higher in colorectal cancer patients (164+/-11 nmol/min mL) than those obtained from normal individuals (92+/- 23 nmol/min mL). CONCLUSIONS: GSTs measurement may be useful as a colorectal cancer marker in colorectal cancer, and biopsies obtained at colonoscopy can be used to measure tumor markers.

Adult↗
PubMed2006

The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin.

Glutathione S-transferases (GSTs) are multifunctional detoxification proteins that protect the cell from electrophilic compounds. Overexpression of GSTs in cancer results in resistance to chemotherapeutic agents and inhibition of the over expressed GST has been suggested as an approach to combat GST-induced resistance. The inhibition of human recombinant GSTs by natural plant products was investigated in this study. Using 1-chloro-2,4 dinitrobenzene (CDNB) as a substrate, ellagic acid and curcumin were shown to inhibit GSTs A1-1, A2-2, M1-1, M2-2 and P1-1 with IC(50) values ranging from 0.04 to 5 microM whilst genistein, kaempferol and quercetin inhibited GSTs M1-1 and M2-2 only. The predominant mode of inhibition with respect to the G and H-sites were mixed inhibition and uncompetitive to a lesser extent. The K(i) (K(i)(')) values for ellagic acid and curcumin with respect to GSH and CDNB were in the range 0.04-6 microM showing the inhibitory potency of these polyphenolic compounds. Ellagic acid and curcumin also showed time- and concentration-dependent inactivation of GSTs M1-1, M2-2 and P1-1 with curcumin being a more potent inactivator than ellagic acid. These results facilitate the understanding of the interaction of human GSTs with plant polyphenolic compounds with regards to their role as chemomodulators in cases of GST-overexpression in malignancies.

Curcumin↗
PubMed2005

Plant glutathione transferases.

Soluble plant glutathione transferases (GSTs) consist of seven distinct classes, six of which have been functionally characterized. The phi and tau class GSTs are specific to plants and the most numerous and abundant of these enzymes. Both have classic conjugating activities toward a diverse range of xenobiotics, including pesticides, where they are major determinants of herbicide selectivity in crops and weeds. In contrast, the zeta and theta class GSTs are conserved in animals and plants and have very restricted activities toward xenobiotics. Theta GSTs function as glutathione peroxidases, reducing organic hydroperoxides produced during oxidative stress. Zeta GSTs act as glutathione-dependent isomerases, catalyzing the conversion of maleylacetoacetate to fumarylacetoacetate, the penultimate step in tyrosine degradation. The other two classes of plant GSTs, the dehydroascorbate reductases (DHARs) and lambda GSTs, differ from phi, tau, zeta, and theta enzymes in being monomers rather than dimers and possessing a catalytic cysteine rather than serine in the active site. Both can function as thioltransferases, with the DHARs having a specialized function in reducing dehydroascorbate to ascorbic acid. The determination of the diverse plant-specific functions of the differing GST classes is described.

Carboxylic Acids↗
PubMed2002

A novel glutathione transferase from Haemophilus influenzae which has high affinity towards antibiotics.

Cytosolic glutathione transferase (GSTs) are a family of multi-functional proteins which catalyse the conjugation of glutathione (GSH) to a large variety of endogenous and exogenous electrophilic compounds. Much is known about cytosolic mammalian GSTs, however, the presence of GSTs in several aerobic and anaerobic micro-organisms has also been demonstrated. Several findings seem to suggest that bacterial GSTs are involved in processes of biodegradation of xenobiotics, including antibiotics. However, the function played by these enzymes in the bacterial cell still remains to be clarified. At present, it is ill-defined whether bacterial GST can be classified, as in the case of mammalian enzymes, into several distinct classes. Here we report the purification of a GST isoform from Haemophilus influenzae using GSH-affinity chromatography. The purified protein was characterised by immunological and kinetic properties different from other known GSTs. The dissociation constants of chloramphenicol, ampicillin, rifampicin and tetracycline to the purified enzyme were 0.62, 9.06, 4.08 and 1.77 microM, respectively, as determined by following the quenching of the protein intrinsic fluorescence. These values were much lower than those previously determined for the same drugs with other mammalian or bacterial GSTs. The present results indicate that the enzyme purified from H. influenzae is a novel GST isoform well distinguished from other known mammalian or bacterial GSTs.

Ampicillin↗
PubMed2004

Proteomic analysis of glutathione S -transferases of Arabidopsis thaliana reveals differential salicylic acid-induced expression of the plant-specific phi and tau classes.

Plant glutathione S -transferases (GSTs) are a large group of multifunctional proteins that are induced by diverse stimuli. Using proteomic approaches we identified 20 GSTs at the protein level in Arabidopsis cell culture with a combination of GST antibody detection, LC-MS/MS analysis of 23-30 kDa proteins and glutathione-affinity chromatography. GSTs identified were from phi, tau, theta, zeta and DHAR sub-sections of the GST superfamily of 53 members. We have uncovered preliminary evidence for post-translational modifications of plant GSTs and show that phosphorylation is unlikely to be responsible. Detailed analysis of GST expression in response to treatment with 0.01-1 mM of the plant defence signal salicylic acid (SA) uncovered some interesting features. Firstly, GSTs appear to display class-specific concentration-dependent SA induction profiles highlighting differences between the large, plant specific phi and tau classes. Secondly, different members of the same class, while sharing similar SA dose responses, may display differences in terms of magnitude and timing of induction, further highlighting the breadth of GST gene regulation. Thirdly, closely related members of the same class ( GSTF6 and GSTF7 ), arising via tandem duplication, may be regulated differently in terms of basal expression levels and also magnitude of induction raising questions about the role of subfunctionalisation within this family. Our results reveal that GSTs exhibit class specific responses to SA treatment suggesting that several mechanisms are acting to induce GSTs upon SA treatment and hinting at class-specific functions for this large and important, yet still relatively elusive gene family.

Arabidopsis↗
PubMed2001

Glutathione S-transferases as antioxidant defence agents confer pyrethroid resistance in Nilaparvata lugens.

Selection of a laboratory colony of the brown planthopper Nilaparvata lugens with the pyrethroids permethrin and lambda-cyhalothrin increased its resistance to both insecticides. Biochemical analysis and synergistic studies with metabolic inhibitors indicated that elevated glutathione S-transferases (GSTs) with a predominant peroxidase activity conferred resistance to both pyrethroids, whereas esterases conferred part of the resistance to permethrin. Purified esterases hydrolysed permethrin at a slow rate, but incubation of either pyrethroid or their primary metabolites with partially purified GSTs had no effect on the metabolic profile. Although GSTs were sensitive to inhibition by both pyrethroids, they did not serve as binding proteins, as previously hypothesized [Grant and Matsumura (1988) Insect Biochem. 18, 615-622]. We demonstrate that pyrethroids, in addition to their neurotoxic effect, induce oxidative stress and lipid peroxidation in insects. Pyrethroid exposure induced lipid peroxides, protein oxidation and depleted reduced glutathione. Elevated GSTs in the resistant strains attenuated the pyrethroid-induced lipid peroxidation and reduced mortality, whereas their in vivo inhibition eliminated their protective role. We therefore hypothesize that the main role of elevated GSTs in conferring resistance in N. lugens is through protecting tissues from oxidative damage. Our study extends the GSTs' range of efficacy to pyrethroid insecticides and possibly explains the role of elevated GSTs in other pyrethroid-resistant insects.

Animals↗
PubMed2001

Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily.

The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions. They have peroxidase and isomerase activities, they can inhibit the Jun N-terminal kinase (thus protecting cells against H(2)O(2)-induced cell death), and they are able to bind non-catalytically a wide range of endogenous and exogenous ligands. Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi and Theta classes on the basis of a combination of criteria such as substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity. Non-mammalian GSTs have been much less well characterized, but have provided a disproportionately large number of three-dimensional structures, thus extending our structure-function knowledge of the superfamily as a whole. Moreover, several novel classes identified in non-mammalian species have been subsequently identified in mammals, sometimes carrying out functions not previously associated with GSTs. These studies have revealed that the GSTs comprise a widespread and highly versatile superfamily which show similarities to non-GST stress-related proteins. Independent classification systems have arisen for groups of organisms such as plants and insects. This review surveys the classification of GSTs in non-mammalian sources, such as bacteria, fungi, plants, insects and helminths, and attempts to relate them to the more mainstream classification system for mammalian enzymes. The implications of this classification with regard to the evolution of GSTs are discussed.

Animals↗
PubMed2004

Reciprocal regulation of glutathione S-transferase spliceforms and the Drosophila c-Jun N-terminal kinase pathway components.

In mammalian systems, detoxification enzymes of the GST (glutathione S-transferase) family regulate JNK (c-Jun N-terminal kinase) signal transduction by interaction with JNK itself or other proteins upstream in the JNK pathway. In the present study, we have studied GSTs and their interaction with components of the JNK pathway from Diptera. We have evaluated the effects of four Delta class Anopheles dirus GSTs, GSTD1-1, GSTD2-2, GSTD3-3 and GSTD4-4, on the activity of full-length recombinant Drosophila HEP (mitogen-activated protein kinase kinase 7; where HEP stands for hemipterous) and the Drosophila JNK, as well as the reciprocal effect of these kinases on GST activity. Interestingly, even though these four GSTs are alternatively spliced products of the same gene and share >60% identity, they exerted different effects on JNK activity. GSTD1-1 inhibited JNK activity, whereas the other three GST isoforms activated JNK. GSTD2-2, GSTD3-3 and GSTD4-4 were inhibited 50-80% by HEP or JNK but GSTD1-1 was not inhibited by JNK. However, there were some similarities in the actions of HEP and JNK on these GSTs. For example, binding constants for HEP or JNK inhibiting a GST were similar (20-70 nM). Furthermore, after incubation of the GSTs with JNK, both JNK and the GSTs changed catalytic properties. The substrate specificities of both GSTs and JNK were also altered after their co-incubation. In addition, glutathione modulated the effects of JNK on GST activity. These results emphasize that different GST spliceforms possess different properties, both in their catalytic function and in their regulation of signalling through the JNK pathway.

Alternative Splicing↗
PubMed1998

Human glutathione S-transferases.

Human glutathione S-transferases (GSTs) are a functionally diverse family of soluble enzymes of detoxification that use reduced glutathione (GSH) in conjugation and reduction reactions. Toxic electrophiles, including a variety of carcinogens, are substrates for the GSTs and after conjugation or reduction they are more easily excreted into bile or urine. Many of the GSTs have been cloned, and the three-dimensional structures of GSTs from several species, including humans, have been determined. These data have provided significant insight into how the GSTs function as enzymes. Many GST substrates are inducers of GST gene expression; nonsubstrate inducers include H2O2 and other reactive oxygen species. The regulatory elements of several human GST genes have been partially characterized, and the regulation of the GSTs in humans appears to be very different from that in rodents. Several polymorphisms of GST expression occur commonly in humans and have been associated with an increased susceptibility to certain cancers, particularly when combined with other genetic and environmental factors such as smoking. The role of GSTs in protecting cells from injury by toxic electrophiles continues to be developed.

Animals↗
PubMed1997

Cloning and localization of a glutathione S-transferase class I gene from Anopheles gambiae.

1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) resistance in both adults and larvae of Anopheles gambiae is mediated by stage-specific glutathione S-transferases (GSTs). On the basis of their biochemical characteristics the larval resistance-associated GSTs are likely to be insect class I GSTs. Aggst1-2, a class I GST gene, which is expressed in larvae, has been cloned from the malaria vector A. gambiae. The gene was inserted into a bacterial expression system, and the detection of 1-chloro-2,4-dinitrobenzene (CDNB) conjugating activity in Eschericia coli expressing the recombinant enzyme confirmed that aggst1-2 encodes a catalytically active GST. The gene encodes a 209 amino acid protein with 46% sequence similarity to a Drosophila melanogaster class I GST (GST-D1), 44% similarity with a Musca domestica class I GST (MdGST-1), but only low levels of homology with class II insect GSTs, including the adult specific AgGST2-1 from A. gambiae. Southern analysis of genomic DNA indicated that A. gambiae has multiple class I GSTs. In situ hybridization of class I genomic and cDNA clones to polytene chromosomes identified a single region of complementarity on chromosome 2R division 18B, suggesting that these class I GSTs in A. gambiae are arranged sequentially in the genome. Three positive overlapping recombinant clones were identified from an A. gambiae genomic library. Mapping and partial sequencing of these clones suggests that there are several GSTs and truncated GST pseudogenes within the 30kb of DNA that these clones span.

Amino Acid Sequence↗
PubMed1992

Expression of alpha, mu and pi class glutathione S-transferases in oval and ductal cells in liver of rats placed on a choline-deficient, ethionine-supplemented diet.

Expression of the alpha, mu and pi class glutathione S-transferases (GSTs) in hepatocytes, oval cells and ductal cells derived from the livers of rats placed on a choline-deficient, ethionine-supplemented (CDE) diet for 5 weeks was investigated. An overall decrease in the expression of alpha and mu class GSTs and an over-expression of pi class GST was observed in the liver after CDE treatment as indicated by Northern blotting analysis. Massive disruption of the liver with oval cell infiltration in the sinusoids throughout the lobule occurred after 5 weeks CDE treatment. 'Duct-like' structures consisting of oval-like cells (ductal cells) with rounder nuclei and more cytoplasm than oval cells within the sinusoids were also apparent. Immunocytochemical analysis revealed that the altered expression of GST in the whole liver is attributed to a differential expression of alpha, mu and pi class GSTs in the different cell types in the liver, including hepatocytes, oval cells around the portal region and among the sinusoids, and oval-like cells (ductal cells) in the 'duct-like' structures. In vitro studies using purified oval-ductal cells and hepatocyte populations confirmed the differential expression of GSTs in the varying cell populations in situ. The expression of the alpha and mu class GSTs in hepatocytes does not appear to be altered by the CDE diet. Heterogeneity in distribution of pi class GST was observed in the hepatocyte population, some hepatocytes were stained strongly while no staining was observed in others. Oval and ductal cells represent two distinct populations displaying different expression of GSTs. Pi class GST was detected in the majority of oval and ductal cells. Alpha class GST was detected in < 5% of the oval cell population and was found in > 50% of the ductal cell population. In contrast, mu class GST was absent in ductal cells and was present in 24% of oval cells around the portal region. This supports the view that ductal cells are not of bile ductal origin since mu GST is present in normal bile duct epithelial cells. Furthermore the change in expression of GSTs in the liver after CDE treatment is attributed to the large increase in oval and ductal cell populations.

Animals↗
PubMed2004

Biotransformation of methyl parathion by glutathione S-transferases.

The organo(thio)phosphate esters are one of the most widely used classes of insecticides. Worldwide, organophosphate insecticides (OPs) result in numerous poisonings each year. In insects, glutathione S-transferases (GSTs) play an important role in OP resistance; limited data suggest that GST-mediated O-dealkylation occurs in humans as well. To characterize the capacity of mammalian GSTs to detoxify OPs, we investigated mammalian GST biotransformation of the widely used OP, methyl parathion (MeP). Cytosolic fractions isolated from rat, mouse, and ten individual adult human livers biotransformed 300 microM MeP at rates of 2.36, 1.76, and 0.70 (mean rate) nmol desmethyl parathion/min/mg, respectively. Our study focused on human GSTs; in particular, we investigated hGSTs M1-1 and T1-1, since deletion polymorphisms occur commonly in these genes. However, we found no correlation between hGSTM1/T1 genotypes and MeP O-dealkylation activities of the ten human liver cytosolic samples. We also measured MeP O-dealkylation activities of several purified recombinant GSTs belonging to the alpha (human GSTs A1-1 and A2-2, mouse GSTA3-3, rat GSTA5-5), mu (human GSTs M1a-1a, M2-2, M3-3, M4-4), pi (human GSTP1-1, mouse GSTs P1-1, P2-2), and theta (human GSTT1-1) classes. At 1 mM glutathione and 300 microM MeP concentrations, hGSTT1-1 and hGSTA1-1 exhibited the highest O-dealkylation activities: 545.8 and 65.0 nmol/min/mg, respectively. When expression level and enzymatic activity are considered, we estimate that hGSTA1-1 is responsible for the majority of MeP O-dealkylation in human hepatic cytosol. In target organs such as brain and skeletal muscle, where hGSTT1-1 is expressed, hGSTT1-1-mediated biotransformation of MeP may be important.

Adolescent↗
PubMed2005

Gold trichloride and gold sodium thiosulfate as markers of contact allergy to gold.

The usefulness of a trivalent gold salt, gold trichloride (GTC), was evaluated as a marker of contact allergy to gold. Patients patch test-positive or patch test-negative to gold sodium thiosulfate (GSTS), 13 subjects of each, were patch tested with dilution series of GTC and equimolar concentrations of GSTS. In order to avoid false-positive and false-negative test reactions, the salts were buffered and placed on polypropene chambers. Allergic reactions were registered in 9/13 gold-allergic patients with GSTS and in 2/13 with GTC. The sum of positive reactions was 18 with GSTS and 5 with GTC. Irritant reactions were none with GSTS and 2 with GTC in the gold-allergic patients. It is concluded that GTC can elicit positive patch test reactions in patients with gold allergy but to a lesser degree when compared with GSTS. Thus, GTC cannot be recommended in patch testing, and GSTS is still the test agent of choice.

Aged↗