Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the main components in the waste products from vinyl chloride industries (EDC-tar), is ethylene dichloride (1,2-dichloroethane). This compound has been tested for mutagenicity on Salmonella typhimurium TA 1535. It is concluded that 1,2-dichloroethane gives a weak direct mutagenic effect, which is enhanced by addition of the postmitochondrial liver fraction (S-9). This activation is NADPH-independent and non microsomal. It is caused by a factor in the soluble fraction (115 000 g supernatant). This activation was further enhanced by the addition of glutathione but not by the addition of L-cysteine, N-acetyl-L-cysteine or 2-mercaptoethanol. No activation was observed when glutathione was added in the presence of a totally denaturated S-9 fraction or in the absence of this fraction. Activation of 1,2-dichloroethane was also found in the presence of glutathione and glutathione S-transferase A and C but not with glutathione S-tranferase B. A synthetic conjugate S-(2-chloroethyl)-L-cysteine gave a strong direct mutagenic effect at concentrations where no effects were seen with 1,2-dichloroethane. It is thus concluded that 1,2-dichloroethane is activated by conjugation to glutathione. Another main component in EDC-tar, 1,1,2-trichloroethane, was not mutagenic under any of our experimental conditions. For comparison 1,2-dibromoethane was also tested and gave a stronger direct mutagenic effect than 1,2-dichloroethane. Like the latter 1,2-dibromoethane was also activated by a NADPH-independent process.
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PMID:The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium I. Activation through conjugation with glutathion in vitro. 2 3

The pretreatment of rat liver mitochondria with alkylating agents (N-ethylmaleimide, iodoacetamide or vinyl pyridine) increased the activity of mitochondrial glutathione transferase (GST) by 100-250%. Further experiments provided evidence that mitochondrial membranes contain an enzymatically inactive protein which can be alkylated through its sulfhydryl groups. By alkylation, this protein achieves catalytic properties similar to those of native GST.
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PMID:Mitochondrial glutathione transferases. The alkylation of mitochondrial membrane yields a catalyst with glutathione-transferase-like properties. 379 Feb 61

Rats were subjected to 4 h continuous and intermittent exposure to vinyl chloride (VC) at the time-weighted average concentration of 50,000 mg/m3. Prior to exposure, half of the animals obtained water, whereas the other half 0.1% sodium phenobarbital (PB) solution for seven consecutive days. The studies were focussed on: body weight, liver weight, activity of enzymes in the blood serum, activity of glutathione S-transferase in the liver cytoplasmatic and microsomal fraction, content of free non-protein sulfhydryl groups (NPSH) in the liver and urinary excretion of thiodiglycolic acid (TDGA). VC exposure, both continuous and intermittent, resulted in a decrease of body weight, NPSH depletion in the liver and TDGA urinary excretion. PB effects were manifested by the persistent decrease in rats' body weight, increase in the liver weight, increase in the cytoplasmatic activity of glutathione S-transferase in the liver and increase in TDGA urinary excretion. With none of the tested parameters, except TDGA, statistically significant differences between the continuous and intermittent VC exposure at the same time-weighted average concentration of 50,000 mg/m3, were found. TDGA urinary excretion was higher in rats poisoned in continuous exposure, as compared to the intermittent one.
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PMID:Comparison of the impact of continuous and intermittent exposure to vinyl chloride, including phenobarbital effect. 402 Jan 14

The mechanism of hexachloro-1:3-butadiene (HCBD)-induced glutathione depletion in male and female rats has been investigated in rat liver and kidney preparations in vitro in order to characterize the enzymes involved and to study the relationship between this effect and the nephrotoxic action of this compound. HCBD caused a marked reduction in glutathione concentration when incubated with male or female hepatic microsomal or cytosolic fractions fortified with glutathione. In contrast with that reported for other halo-olefin's, the depletion of glutathione in the microsomal fraction is not related to the formation of metabolites via cytochrome P-450. The microsomal rate of depletion appeared to be due to a direct reaction catalyzed by a microsomal glutathione S-transferase. A glutathione adduct of HCBD was isolated by thin-layer chromatography and mass spectral analysis strongly indicates the structure to be as S-(1,1,2,3,4-pentachloro-1,3-butadienyl)glutathione, confirming a direct substitution reaction without prior oxidation. This conjugate was formed at a faster rate by the hepatic microsomal fraction than by the cytosolic fraction suggesting a major role for the microsomal glutathione S-transferases in the disposition of this compound. A second more polar glutathione-dependent adduct which may be a double conjugate was formed with cytosol. Glutathione adducts were also formed by male and female kidney cytosol and microsomal fractions but at a slower rate than in liver fractions. It is suggested that the glutathione conjugate of HCBD may be converted to the cysteine derivative, the structure of which is similar to that of S-dichloro-vinyl-L-cysteine and therefore may be nephrotoxic by a similar mechanism.
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PMID:Role of microsomal and cytosolic glutathione S-transferases in the conjugation of hexachloro-1:3-butadiene and its possible relevance to toxicity. 669 3

In search of compounds with improved specificity for targeting the important cancer-associated P1-1 glutathione S-transferase (GST) isozyme, new analogs 4 and 5 of the previously reported glutathione S-transferase (GST)-activated latent alkylating agent gamma-glutamyl-alpha-amino-beta-[[[2-[[bis[bis(2-chloroethyl)amino]ph osp horyl]oxy]ethyl]sulfonyl]propionyl]-(R)-(-)-phenylglycine (3) have been designed, synthesized, and evaluated. One of the diastereomers of 4 exhibited good selectivity for GST P1-1. The tetrabromo analog 5 of the tetrachloro compound 3 maintained its specificity and was found to be more readily activated by GSTs than 3. The GST activation concept was further broadened through design, synthesis, and evaluation of a novel latent urethane mustard 8 and its diethyl ester 9. Interestingly, 8 showed very good specificity for P1-1 GST. Cell culture studies were carried out on 4, 5, 8, and 9 using cell lines engineered to have varying levels of GST P1-1 isozyme. New analogs 4 and 5 exhibited increased toxicity to cell lines with overexpressed GST P1-1 isozyme. The urethane mustard 8 and its diethyl ester 9 were found to be not as toxic. However, they too exhibited more toxicity to a cell line engineered to have elevated P1-1 levels, which was in agreement with the observed in vitro specificity of 8 for P1-1 GST isozyme. Mechanistic studies on alkaline as well as enzyme-catalyzed decomposition of latent mustard 3 provided experimental proof for the hypothesis that 3 breaks down into an active phosphoramidate mustard and a reactive vinyl sulfone. The alkylating nature of the decomposition products was further demonstrated by trapping those transient species as relatively stable diethyldithiocarbamic acid adducts. These results substantially extend previous efforts to develop drugs targeting GST and provide a paradigm for development of other latent drugs.
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PMID:Design, synthesis, and evaluation of latent alkylating agents activated by glutathione S-transferase. 864 13

Vinyl chloride monomer (VCM) is hepatotoxic as well as carcinogenic in humans. There are reports that exposure to VCM seems to induce abnormal liver function, liver fibrosis, cirrhosis, portal hypertension, and angiosarcoma of the liver. In vivo, VCM is metabolized by cytochrome P450 2E1 (CYP2E1) to form the electrophilic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), which may either cause cell damage or be further metabolized and detoxified by glutathione S-transferases (GSTs). This study investigated whether or not the genotypes CYP2E1, glutathione S-transferase theta (GST T1) and mu (GST M1) correlated with abnormal liver function found in vinyl chloride exposed workers. For this study, 251 workers from five polyvinyl chloride plants were enrolled. The workers were classified into two exposure groups (high and low) and the degree of exposure was determined based on their job titles and airborne VCM concentration. The activity of serum alanine aminotransferase (ALT) was used as the parameter of liver function. The genotypes CYP2E1, GST T1 and GST M1 were determined by polymerase chain reaction and restriction fragment length polymorphism on peripheral white blood cell DNA. Other potential risk factors were also ascertained and the confounding effect was adjusted accordingly. Stratified analyses were used to explore the correlation between the alteration of liver function and the genotypes CYP2E1, GST T1 and GST M1 among the workers exposed to different levels of VCM. The following results were obtained (1) at low VCM exposure, the odds ratio (OR) of positive GST T1 on abnormal ALT was 3.8 (95% CI 1.2-14.5) but the CYP2E1 genotype was not associated with abnormal ALT. (2) At high VCM exposure, a c2c2 CYP2E1 genotype was associated with increased OR on abnormal ALT (OR 5.4, 95% CI 0.7-35.1) and positive GST T1 was significantly associated with decreased OR on abnormal ALT (OR 0.3, 95% CI 0.1-0.9). (3) Multiple linear and logistic regression also showed strong interactions of the VCM exposure to CYP2E1 as well as to the GST T1 genotype. These observations suggest that the two genotypes, CYP2E1 and GST T1, may play important roles in the biotransformation of VCM, the effect of which leads to liver damage.
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PMID:The GST T1 and CYP2E1 genotypes are possible factors causing vinyl chloride induced abnormal liver function. 924 25

Hexachloro-1,3-butadiene (HCBD) is nephrotoxic in rats. Its toxicity is due to a multistep bioactivation pathway involving glutathione conjugation. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine resulting from further processing of the GSH conjugate of HCBD is oxidized in vitro and in vivo to the corresponding sulfoxide diastereomers by cytochromes P450 3A. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide diastereomers represent vinyl sulfoxides which are electrophiles. They are analogous to alpha,beta-unsaturated carbonyl compounds and may be conjugated with glutathione. This study presents experimental data for the different reactivity of the two diastereomers of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with glutathione S-transferases in vitro. The structures of the individual diastereomers were assigned by stereoselective oxidation of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine with sodium periodate in the presence of chloroperoxidase. The two isolated diastereomers were incubated with rat liver and kidney cytosol in the presence of glutathione. In incubations with rat liver cytosol, the formation of a glutathione conjugate, which was identified as (R)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, was observed with the (R)-sulfoxide diastereomer. The enzymatic reaction of the (S)-sulfoxide diastereomer with glutathione resulted in two GSH conjugates identified as (S)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide and (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide. In rat kidney cytosol only the S-diastereomer of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide is transformed to (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, while transformation of the R-diastereomer to glutathione conjugates was not observed. In rat kidney cytosol, the rates of formation of (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide from conjugation of the S-diastereomer were comparable to those in rat liver cytosol. Incubation of (S)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with purified rat and human glutathione S-transferases indicates that both R- and S-diastereomers were conjugated to the corresponding 1,4-disubstituted compounds by mu-glutathione S-transferases. Formation of the 1,2-disubstituted conjugation product of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide was catalyzed exclusively by alpha-glutathione S-transferases. These results are one of the first examples for differences in regio- and stereospecificity in reactions catalyzed by different glutathione S-transferase enzymes.
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PMID:Stereo- and regioselective conjugation of S-halovinyl mercapturic acid sulfoxides by glutathione S-transferases. 947 21

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

Acrylonitrile (AN) is an industrial vinyl monomer that is acutely toxic. When administered to rats, AN covalently binds to tissue proteins in a dose-dependent but nonlinear manner [Benz, F. W., Nerland, D. E., Li, J., and Corbett, D. (1997) Fundam. Appl. Toxicol. 36, 149-156]. The nonlinearity in covalent binding stems from the fact that AN rapidly depletes liver glutathione after which the covalent binding to tissue proteins increases disproportionately. The identity of the tissue proteins to which AN covalently binds is unknown. The experiments described here were conducted to begin to answer this question. Male Sprague-Dawley rats were injected subcutaneously with 115 mg/kg (2.2 mmol/kg) [2,3-(14)C]AN. Two hours later, the livers were removed, homogenized, and fractionated into subcellular components, and the radioactively labeled proteins were separated on SDS-PAGE. One set of labeled proteins was found to be glutathione S-transferase (GST). Specific labeling of the mu over the alpha class was observed. Separation of the GST subunits by HPLC followed by scintillation counting showed that AN was selective for subunit rGSTM1. Mass spectral analysis of tryptic digests of the GST subunits indicated that the site of labeling was cysteine 86. The reason for the high reactivity of cysteine 86 in rGSTM1 was hypothesized to be due to its potential interaction with histidine 84, which is unique in this subunit.
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PMID:Covalent binding of acrylonitrile to specific rat liver glutathione S-transferases in vivo. 1145 25

Mutant p53 protein and anti-p53 antibody in circulating blood can be detectedamong individuals with mutations of the p53 tumor suppressor gene. Plasma mutant p53 protein and anti-p53 antibody have also been associated with vinyl chloride monomer (VCM) exposure, although the mechanism of VCM-related carcinogenesis remains unclear. Polymorphisms of metabolic and DNA repair genes have been implicated in chemical exposure-related carcinogenesis. The aim of this study is to explore the association between polymorphisms of metabolic and DNA repair genes with mutant p53 protein and anti-p53 antibody expression induced by VCM. Study subjects comprised 333 male workers occupationally exposed to VCM. Plasma mutant p53 protein and anti-p53 antibody detected with ELISA were grouped together as p53 overexpression. Genotypes of cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), glutathione S-transferase T1 (GSTT1), and X-ray repair cross-complementing group 1 (XRCC1, exon 10) genes were identified by the PCR. High VCM exposure group had significantly higher p53 overexpression as compared with low exposure group [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1-3.8]. Individuals having experienced a high VCM exposure and displaying a XRCC1 Gln-Gln genotype had a highest risk of p53 overexpression among those having different combinations of VCM exposure and XRCC1 genotypes (OR, 6.5; 95% CI, 1.7-24.2). Interestingly, those subjects reflecting a CYP2E1 c2c2 genotype among the low VCM-exposure group demonstrated a greater risk of p53 overexpression (OR, 9.8; 95% CI, 1.2-81.6) as compared with those experiencing a low VCM exposure and CYP2E1 c1c1/c1c2 genotypes. Additional analysis revealed that individuals possessing more susceptible XRCC1 Gln-Gln, CYP2E1 c2c2, ALDH2 1-2/2-2, and non-null GSTT1 genotypes were more likely to reveal p53 overexpression. Our results suggest that susceptible XRCC1 and CYP2E1 genotypes may modulate the mutation of the p53 gene among VCM-exposed workers.
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PMID:XRCC1 and CYP2E1 polymorphisms as susceptibility factors of plasma mutant p53 protein and anti-p53 antibody expression in vinyl chloride monomer-exposed polyvinyl chloride workers. 1201 Aug 62


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