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  • 1
    ISSN: 1520-5010
    Source: ACS Legacy Archives
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 116 (1994), S. 1603-1609 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: Key words Trichloroethene ; Renal cell cancer ; GSTM1 ; GSTT1 ; Glutathione transferases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 gene (GSTM1+) and 18 at least one functional GSTT1 gene (GSTT1+). Among the 48 reference workers, 17 were GSTM1+ and 31 were GSTT1+. Odds ratios for renal cell cancer were 2.7 for GSTM1+ individuals (95% CI, 1.18–6.33; P 〈 0.02) and 4.2 for GSTT1+ individuals (95% CI, 1.16–14.91; P 〈 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0738
    Keywords: Key words Acrylonitrile ; Ethylene oxide ; Haemoglobin adducts ; Glutathione transferase (GST) polymorphisms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine, MV; N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 μg CEV/l blood; 6.7 and 6.7 μg MV/l blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1− individuals compared to GSTT1+ persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST− individuals displayed adduct levels that were about 1/3 higher than those of GSTT1+ individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1− and GSTT1+ persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1− persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0738
    Keywords: Key words Glutathione transferase ; GSTT1 ; GSTM1 ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Glutathione transferases are known to be important enzymes in the metabolism of xenobiotics. In humans genetic polymorphisms have been reported for the hGSTM1 and hGSTT1 genes leading to individual differences in susceptibility towards toxic effects, such as cancer. This study describes the distribution of the two polymorphisms of hGSTT1 and hGSTM1 in the normal Chinese population of Shanghai. Out of 219 healthy individuals having been genotyped for GSTT1 and GSTM1, 108 (49%) were identified to be homozygously deficient for the GSTT1 gene and 107 (49%) for the GSTM1 gene.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0738
    Keywords: Key words Thymidine glycol ; DNA damage ; Reactive oxygen species ; Renal ischaemia ; Kidney transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Reactive oxygen species are generated during ischaemia-reperfusion of tissue. Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted in urine and can be used as biomarker of oxidative DNA damage. Time dependent changes in urinary excretion rates of thymidine glycol were determined in six patients after kidney transplantation and in six healthy controls. A new analytical method was developed involving affinity chromatography and subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column chemical reaction detector and endpoint fluorescence detection. The detection limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which corresponds to about half of the physiological excretion level in healthy control persons. After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum around 48 h. The excretion rate remained elevated until the end of the observation period of 10 days. Severe proteinuria with an excretion rate of up to 7.2 g of total protein per mmol creatinine was also observed immediately after transplantation and declined within the first 24 h of allograft function (0.35 ± 0.26 g/mmol creatinine). The protein excretion pattern, based on separation of urinary proteins on sodium dodecyl sulphate-polyacrylamide gel electrophorosis (SDS-PAGE), as well as excretion of individual biomarker proteins, indicated nonselective glomerular and tubular damage. The increased excretion of thymidine glycol after kidney transplantation may be explained by ischaemia-reperfusion induced oxidative DNA damage of the transplanted kidney.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0738
    Keywords: Key words Ethylene oxide ; Propylene oxide ; Butylene oxide ; Methyl bromide ; Glutathione transferase theta
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The transformation of ethylene oxide (EO), propylene oxide (PO) and 1-butylene oxide (1-BuO) by human glutathione transferase theta (hGSTT1–1) was studied comparatively using `conjugator' (GSTT1+ individuals) erythrocyte lysates. The relative sequence of velocity of enzymic transformation was PO 〉 EO » 1-BuO. The faster transformation of PO compared to EO was corroborated in studies with human and rat GSTT1–1 (hGSTT1–1 and rGSTT1–1, respectively) expressed by Salmonella typhimurium TA1535. This sequence of reactivities of homologous epoxides towards GSTT1–1 contrasts to the sequence observed in homologous alkyl halides (methyl bromide, MBr; ethyl bromide, EtBr; n-propyl bromide, PrBr) where the relative sequence MeBr » EtBr 〉PrBr is observed. The higher reactivity towards GSTT1–1 of propylene oxide compared to ethylene oxide is consistent with a higher chemical reactivity. This is corroborated by experimental data of acid-catalysed hydrolysis of a number of aliphatic epoxides, including ethylene oxide and propylene oxide and consistent with semi-empirical molecular orbital modelings.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0738
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The presence of theta-class glutathione S-transferase (GST) in marmoset monkey liver cytosol was investigated. An anti-peptide antibody targeted against the C-terminus of rGSTT1 reacted with a single band in marmoset liver cytosol that corresponded to a molecular weight of 28 kDa. The intensity of the immunoreactive band was not affected by treatment of marmoset monkeys with 2,3,7,8-tetrachlorodibenzo-p-dioxin, phenobarbitone, rifampicin or clofibric acid. Similarly, activity towards methyl chloride (MC) was unaffected by these treatments. However, GST activity towards 1,2-epoxy- 3-(p-nitrophenoxy)-propane (EPNP) was increased in marmosets treated with phenobarbitone (2.6-fold) and rifampicin (2.6-fold), activity towards dichloromethane (DCM) was increased by 50% after treatment of marmosets with clofibric acid, and activity towards 1-chloro-2,4-dinitrobenzene (CDNB) was raised slightly (30–42% increases) after treatment with phenobarbitone, rifampicin or clofibric acid. Compared with humans, marmoset liver cytosol GST activity towards DCM was 18-fold higher, activity towards MC was 7 times higher and activity towards CDNB was 4 times higher. Further, EPNP activity was clearly detectable in marmoset liver cytosol samples, but was undetectable in human samples. Immunoreactive marmoset GST was partially purified by affinity chromatography using hexylglutathione-Sepharose and Orange A resin. The interaction of immunoreactive marmoset GST was similar to that found previously for rat and human GSTT1, suggesting that this protein is also a theta class GST. However, unlike rat GSTT1, the marmoset enzyme was not the major catalyst of EPNP conjugation. Instead, immunoreactivity was closely associated with activity towards MC. In conclusion, these results provide evidence for the presence of theta-class GST in the marmoset monkey orthologous to rGSTT1 and hGSTT1.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0738
    Keywords: Key words Glutathione transferase ; GSTT1-1  ;   Polymorphism  ;  Methyl chloride  ;   Dichloromethane  ;   1 ; 2-Epoxy-3-(p-nitrophenoxy) propane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse 〉 HC 〉 rat 〉 LC 〉 hamster 〉 NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation␣between species was mouse 〉 rat 〉 HC 〉 LC 〉 hamster 〉 NC for liver, but mouse 〉 HC 〉 LC/ rat 〉 hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0738
    Keywords: Key words Glutathione transferase GSTT1 ; Methyl chloride ; Tissue specificity ; Radiometric assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A new system has been developed to determine enzyme activities of glutathione transferase θ (GSTT1-1) based on radiometric product detection resulting from the enzymic reaction of methyl chloride with 35S-labelled glutathione. In principle, the method is universally applicable for determination of glutathione transferase activities towards a multiplicity of substrates. The method distinguishes between erythocyte GSTT1-1 activities of human `non-conjugators', `low conjugators' and `high conjugators'. Application to cytosol preparations of livers and kidneys of male and female Fischer 344 and B6C3F1 mice reveals differential GSTT1-1 activities in hepatic and renal tissues. These ought to be considered in species-specific modellings of organ toxicities of chlorinated hydrocarbons.
    Type of Medium: Electronic Resource
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