Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Airway epithelial surface is the primary target of airborne pollutants. To estimate the distribution of xenobiotic-metabolizing enzymes in the respiratory tract of dogs, epithelia from different airway sites of four animals were analyzed for metabolism of sulfite (sulfite oxidase) and formaldehyde (formaldehyde dehydrogenase and aldehyde dehydrogenase). In addition, glutathione S-transferases were assayed using several model substrates. Enzyme activities were compared with those found in liver parenchyma. The activity of sulfite oxidase was found to be comparable in nose, trachea, and proximal and medium bronchi, but appeared to be lower in lung parenchyma of most animals. In contrast, hepatic sulfite oxidase activity of these animals was substantially higher compared to that in airway epithelia. The activity of glutathione-dependent formaldehyde dehydrogenase (FDH) appeared to be highest in nose and lowest in distal bronchi, lung, and liver parenchyma. The distribution pattern of the glutathione-independent aldehyde dehydrogenase (AldDH) in the respiratory tract was different from that of FDH. Levels of AldDH were about 5- to 10-fold lower than those of FDH, suggesting that AldDH is of minor importance for pulmonary formaldehyde detoxification. With regard to ethanol detoxification by a class I alcohol dehydrogenase (ADH), no measurable enzyme activity could be detected at most respiratory sites contrary to the high activity found in liver parenchyma. Regarding glutathione S-transferases (GSTs), different distributions of enzyme activities were found in the large and small airways when using three substrates. The 1-chloro-2,4-dinitrobenzene (CDNB)-related activities in the cytosolic fraction of the upper (nose, trachea) and lower airways (proximal, medium and distal bronchi) were higher than those in the microsomal fraction. Interestingly, there was no difference between CDNB-related activities in the cytosolic and microsomal fraction of the liver. Highest cytosolic activities were found in the nose, and were comparable to those detected in the liver parenchyma. The cytosolic 1,2-dichloro-4-nitrobenzene (DCNB)-related activities in the nose, proximal bronchi, and lung parenchyma were appeared to be markedly higher than those in trachea and medium and distal bronchi, while the microsomal activities were not detectable at most respiratory sites. In contrast, distinctly higher activities were measured in both fractions of liver tissue. Cytosolic 1, 2-epoxy-3-(p-nitrophenoxy)-propane (EPNP)-related activities were present in upper and lower airways including lung parenchyma at comparable levels, while in liver tissue the mean activities were distinctly lower. No EPNP-related activities were found in the microsomal fractions. In conclusion, most xenobiotic-metabolizing enzymes investigated in this study could be detected in epithelia of various respiratory sites. The most outstanding result revealed higher levels of FDH activity in the nose and downstream to the medium bronchi in comparison to those found in the small airways, lung, and liver tissue. Similarly, the EPNP-related GST exhibited a distinctly higher activity at all respiratory sites compared to the activity in liver tissue, suggesting a different regulation of this enzyme in lung and liver.
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PMID:Xenobiotic-metabolizing enzymes in the canine respiratory tract. 1038 Jan 57

It is established that the diverse, multifunctional crystallins are responsible for the optical properties of the cellular, transparent lens of the complex eyes of vertebrates and invertebrates. Lens crystallins often differ among species and may be enzymes or stress proteins. I present here the idea that abundant water-soluble enzymes and other proteins may also be used for cellular transparency in the epithelial cells and, possibly, stromal keratocytes of the cornea. Aldehyde dehydrogenases and transketolase are among the putative "corneal crystallins" in mammals, and gelsolin may be a corneal crystallin in the zebrafish. In invertebrates, the glutathione S-transferase-related S-crystallins of the lens appear to be used also as corneal crystallins in the squid, and an aldehyde dehydrogenase-related protein is the crystallin in the lens and, possibly, cornea of the scallop. The use of abundant, taxon-specific water-soluble proteins as crystallins for cellular transparency in the cornea would provide a new conceptual link between this tissue and the lens.
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PMID:Review: A case for corneal crystallins. 1080 28

Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), N-acetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.
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PMID:Polymorphism of drug-metabolizing enzymes in relation to individual susceptibility to industrial chemicals. 1081 37

We investigated 191 patients with oral cancer (121 males and 70 females) and 121 non oral cancer patients (69 males and 52 females), both groups with a history of alcohol use. Blood was analyzed with aldehyde dehydrogenase 2 (ALDH 2) and glutathione S-transferase M 1 (GSTM 1) genotyping. ALDH 2 genotyping was performed by polymerase chain reaction (PCR)-Restriction fragment length polymorphism (RFLP) method and GSTM 1 genotyping was amplified with PCR using GSTM 1 specific primers. In the oral cancer group, the alcohol-drinking rate (59.7%) was significantly higher than in the non cancer group (alcohol-drinking rate 27.3%, p < 0.01). The incidence of inactive ALDH 2 and GSTM 1 in the cancer group with an alcohol-drinking habit was 34.2 and 67.5% and was higher than in the non cancer group with an alcohol-drinking habit (15.1, 45.5%).
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PMID:Aldehyde dehydrogenase 2 and glutathione S-transferase M 1 polymorphisms in relation to the risk for oral cancer in Japanese drinkers. 1088 18

During oxidative stress, reactive aldehydes, including trans-4-hydroxy-2-nonenal (4-HNE), are generated by peroxidation of membrane lipids and purportedly stimulate hepatic stellate cells to produce excessive extracellular matrix, including type I collagen. An important question concerning the ability of 4-HNE to modulate collagen production by stellate cells is the potential of these specialized cells to detoxify 4-HNE. The objective of the present study was to characterize the ability of stellate cell lines, derived from normal (NFSC) and cirrhotic (CFSC) rat livers, to metabolize 4-HNE by oxidative, reductive and conjugative pathways. These two stellate cell lines were noted to have differing susceptibilities to the cytotoxic effect of 4-HNE. Treatment of both stellate cell lines with a range of 4-HNE doses demonstrated that the concentration which was cytotoxic to 50% of CFSC (TD(50)) was 25% greater than that for NFSC (967.57+/-9.26 nmol/10(6) cells vs. 769.90+/-5.32 nmol/10(6) cells respectively). The capacity of these cell lines to metabolizes 4-HNE was determined by incubating them in suspension with 50 microM 4-HNE (10 nmol/10(6) cell); 4-HNE elimination and metabolite formation were quantified over a 20 min time course. Both stellate cell lines rapidly metabolized 4-HNE, with the CFSC line eliminating 4-HNE at a rate that was approx. 2-fold greater than the NFSC line. The rate of 4-HNE metabolism attributable to glutathione S-transferase (GST) was similar in both cell lines, though differential cell specific expressions of GST isoforms GSTP1-1 and GSTA4-4 were observed. The greater rate of 4-HNE elimination by CFSC was attributable to its aldehyde dehydrogenase (ALDH) activity which accounted for approx. 50% of 4-HNE metabolism in CFSC but was insignificant in NFSC. Neither cell line had detectable alcohol dehydrogenase activity or protein levels. Measurement of cellular GSH concentrations revealed that NFSC contain approx. 2-fold greater concentrations of GSH when compared to CFSC and that following 4-HNE treatment, GSH levels were rapidly depleted from both cell lines. Concomitant with 4-HNE mediated GSH depletion, a corresponding increase in the 4-HNE-glutathione adduct formation was observed with the NFSC line forming greater amounts of the glutathione adduct than did the CFSC line. Taken together, these data demonstrate that both stellate cell lines have the capacity to metabolize 4-HNE but that CFSC have a greater rate of metabolism which is attributable to their greater ALDH activity, suggesting that the stellate cells isolated from cirrhotic liver may be differentially responsive to the biologic effects of 4-HNE.
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PMID:Characterization of 4-hydroxy-2-nonenal metabolism in stellate cell lines derived from normal and cirrhotic rat liver. 1101 74

Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.
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PMID:Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer. 1105 19

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
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PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

In guinea-pig liver cytosol, racemic 4-hydroxy-2(E)-nonenal (HNE), a reactive and highly toxic product released from biomembranes by lipid peroxidation, was detoxified (S)-preferentially by GSH conjugation mediated by glutathione S-transferases (GSTs) and (R)-preferentially by NAD(+)-dependent oxidation mediated by aldehyde dehydrogenase (ALDH). The GST-mediated detoxification of the HNE enantiomers proceeded at much higher rates than that mediated by ALDH in guinea-pig liver cytosol. All the major guinea-pig GSTs, A1-1, M1-1, M1-2 and M1-3*, isolated from guinea-pig liver cytosol also catalysed the (S)-preferential conjugation of the HNE enantiomers. The liver and other major tissues of guinea-pigs had no immunologically detectable level of a putative GSTA4-4 orthologue, which exists as a minor GST protein in rat, mouse and human livers and exhibits extremely high catalytic activity towards HNE. All the hepatic rat GSTs, A1-1(2), A1-3, A4-4, M1-1, M1-2 and M2-2, also catalysed the (S)-preferential conjugation of HNE enantiomers.
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PMID:(S)-preferential detoxification of 4-hydroxy-2(E)-nonenal enantiomers by hepatic glutathione S-transferase isoforms in guinea-pigs and rats. 1125 69

Kupffer cells are known to participate in the early events of liver injury involving lipid peroxidation. 4-Hydroxy-2,3-(E)-nonenal (4-HNE), a major aldehydic product of lipid peroxidation, has been shown to modulate numerous cellular systems and is implicated in the pathogenesis of chemically induced liver damage. The purpose of this study was to characterize the metabolic ability of Kupffer cells to detoxify 4-HNE through oxidative (aldehyde dehydrogenase; ALDH), reductive (alcohol dehydrogenase; ADH), and conjugative (glutathione S-transferase; GST) pathways. Aldehyde dehydrogenase and GST activity was observed, while ADH activity was not detectable in isolated Kupffer cells. Additionally, immunoblots demonstrated that Kupffer cells contain ALDH 1 and ALDH 2 isoforms as well as GST A4-4, P1-1, Ya, and Yb. The cytotoxicity of 4-HNE on Kupffer cells was assessed and the TD50 value of 32.5+/-2.2 microM for 4-HNE was determined. HPLC measurement of 4-HNE metabolism using suspensions of Kupffer cells incubated with 25 microLM 4-HNE indicated a loss of 4-HNE over the 30-min time period. Subsequent production of 4-hydroxy-2-nonenoic acid (HNA) suggested the involvement of the ALDH enzyme system and formation of the 4-HNE-glutathione conjugate implicated GST-mediated catalysis. The basal level of glutathione in Kupffer cells (1.33+/-0.3 nmol of glutathione per 10(6) cells) decreased significantly during incubation with 4-HNE concurrent with formation of the 4-HNE-glutathione conjugate. These data demonstrate that oxidative and conjugative pathways are primarily responsible for the metabolism of 4-HNE in Kupffer cells. However, this cell type is characterized by a relatively low capacity to metabolize 4-HNE in comparison to other liver cell types. Collectively, these data suggest that Kupffer cells are potentially vulnerable to the increased concentrations of 4-HNE occurring during oxidative stress.
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PMID:Metabolism of 4-hydroxynonenal by rat Kupffer cells. 1137 Jun 75

Treatment of rats and mice with a single oral dose of dimethyldithiocarbamate (DMDTC; 250 mg/kg) had a marked effect on hepatic CYP2E1 and aldehyde dehydrogenase activities, measured in vitro, for up to 24 h after dosing. The same treatment did not affect CYP2A6, glutathione S-transferase, epoxide hydrolase, alcohol dehydrogenase activities or hepatic glutathione levels. As a consequence of the loss of CYP2E1 activity, butadiene metabolism in liver fractions from DMDTC treated rats and mice was markedly reduced, as was the metabolism of the mono-epoxide to the di-epoxide in mouse liver. The conversion of the mono-epoxide to the diol by epoxide hydrolases was not affected by DMDTC treatment. Urinary excretion of radioactivity, following dosing with DMDTC and exposure to 200 ppm C-14 butadiene for 6 h, was markedly reduced in rats, but increased in mice. The profiles of urinary metabolites were qualitatively similar from mice exposed to butadiene to those exposed after dosing with DMDTC. In the rat, pre-dosing with DMDTC resulted in the formation of three additional urinary metabolites following exposure to butadiene. Overall, DMDTC appears to impact qualitatively and quantitatively on the metabolism of butadiene. The nature and full significance of these changes has yet to be characterised.
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PMID:The influence of co-exposure to dimethyldithiocarbamate on butadiene metabolism. 1139 14


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