Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Thier, Ricarda; Taylor, Jennifer; Pemble, Sally; Humphreys, W. Griffith; Persmark, Magnus; Ketterer, Brian; Guengerich, F. Peter

doi:10.1073/pnas.90.18.8576

Cited by 179 publications

(178 citation statements)

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“…DM11 incubated with glutathione and chlorofluoromethane (6). Chemically synthesized S-chloromethylglutathione alkylated deoxyguanosine in vitro (11), and the main product of this reaction was characterized as S-[1-N 2 -deoxyguanosinylmethyl]glutathione (11,44). Nevertheless, the formation of DNA lesions as a consequence of S-chloromethylglutathione formation during conversion of DCM by DCM dehalogenase-GST remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…On the one hand, DCM-converting GSTs from mammals and methylotrophic bacteria have toxic and mutagenic effects in Salmonella enterica serovar Typhimurium (18,44) and Methylobacterium (18). On the other hand, the massive production of hydrochloric acid by cytosolic DCM dehalogenase during growth with DCM suggests that DCM-degrading methylotrophic bacteria may have evolved efficient systems for the maintenance of intracellular pH and for the excretion of chloride ions.…”

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DNA Polymerase I Is Essential for Growth of Methylobacterium dichloromethanicum DM4 with Dichloromethane

2000

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Methylobacterium dichloromethanicum DM4 grows with dichloromethane as the unique carbon and energy source by virtue of a single enzyme, dichloromethane dehalogenase-glutathione S-transferase. A mutant of the dichloromethane-degrading strain M. dichloromethanicum DM4, strain DM4-1445, was obtained by mini-Tn5 transposon mutagenesis that was no longer able to grow with dichloromethane. Dichloromethane dehalogenase activity in this mutant was comparable to that of the wild-type strain. The site of mini-Tn5 insertion in this mutant was located in the polA gene encoding DNA polymerase I, an enzyme with a well-known role in DNA repair. DNA polymerase activity was not detected in cell extracts of the polA mutant. Conjugation of a plasmid containing the intact DNA polymerase I gene into the polA mutant restored growth with dichloromethane, indicating that the polA gene defect was responsible for the observed lack of growth of this mutant with dichloromethane. Viability of the DM4-1445 mutant was strongly reduced upon exposure to both UV light and dichloromethane. The polA -lacZ transcriptional fusion resulting from mini-Tn5 insertion was constitutively expressed at high levels and induced about twofold after addition of 10 mM dichloromethane. Taken together, these data indicate that DNA polymerase I is essential for growth of M. dichloromethanicum DM4 with dichloromethane and further suggest an important role of the DNA repair machinery in the degradation of halogenated, DNA-alkylating compounds by bacteria.Dichloromethane (DCM) is an organic solvent produced industrially in large amounts for a wide range of technical applications (Halogen Solvents Industry Alliance [http://www .hsia.org/white_papers/methchlor.htm]). Its low boiling point and high solubility in water make it a frequently encountered environmental contaminant (36,46). The toxicity of DCM to mammals continues to be investigated intensively (9,14,21,40,45), but its causes are not yet fully characterized at the molecular level. Many specialized aerobic methylotrophic bacteria have been isolated from soil and groundwater environments contaminated with DCM for their ability to grow with DCM as the sole source of carbon and energy (49). Such bacteria rely on a single enzyme, DCM dehalogenase, for this purpose. DCM dehalogenase, which can make up to 20% of the soluble protein during bacterial growth with DCM, was purified and shown to catalyze the glutathione-dependent transformation of DCM to formaldehyde, used in both biomass and energy production, and to two molecules of hydrochloric acid (31). The corresponding gene dcmA was cloned (33) from Methylobacterium dichloromethanicum DM4 (15) (formerly Methylobacterium sp. strain DM4), Methylophilus sp. strain DM11 (3), and, more recently, from several other DCM-degrading strains (49, 50). Sequence analysis indicates that DCM dehalogenases belong to the glutathione S-transferase (GST) enzyme family (27,47). DCM dehalogenases were the first bacterial GSTs to be characterized, but it is becoming clear that the genom...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

DNA Polymerase I Is Essential for Growth of Methylobacterium dichloromethanicum DM4 with Dichloromethane

2000

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“…In an experimental study, the GSH conjugation of dihalomethanes, such as dichloromethane, which have a similar chemical structure to VCM, has been clearly demonstrated to result in genotoxicity (Thier et al 1993). Garnier et al (1996) reported, after acute inhalation exposure to methyl bromide involving two workers, the GST T1-positive worker showed signs of severe neurotoxicity, whereas the second worker, with GST T1-null genotype, developed only mild neurotoxic symptoms.…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-transferase M1 and GST T1 genetic polymorphisms and Raynaud’s phenomenon in French vinyl chloride monomer-exposed workers

et al. 2006

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Occupational vinyl chloride monomer (VCM) exposure can induce Raynaud's phenomenon (RP). However, not all VCM workers developed RP, which suggests an underlying genetic susceptibility. Genetic polymorphisms of glutathione S-transferases (GSTs), involved in VCM metabolism, have been shown to influence certain VCM-related health effects. We have conducted a case-control study of 58 subjects with RP along with 247 subjects without RP, from a population of 305 French workers exposed or formerly exposed to VCM, to assess any association between GST M1 and GST T1 gene polymorphisms, either separately or in combination, and the presence of RP. None of the GST M1 or GST T1 genotypes were significantly associated with the presence of RP among studied VCM workers. A combination of positive genotypes for both GST M1 and GST T1 was significantly associated with RP presence, compared to the other combinations of genotypes (OR=2.1, 95% CI=1.1-3.8). OR adjusted for age, smoking status, alcohol consumption and history of treated hypertension did not reach significance (OR=2.0, 95% CI=0.9-5.2). None of the GST M1 and GST T1 genotypes seem to contribute separately to the presence of RP, suggesting that they are not, when taken alone, a major determinant of interindividual variability for VCMinduced PR. However, the combination of both positive GST M1 and GST T1 genotypes appears to contribute slightly to susceptibility to RP in VCM-exposed subjects. Nevertheless, our study-the first to examine the role of a genetic component in the occurrence of RP secondary to occupational exposure to a chemical-corroborates the previous considerations that interaction between the genetic constitution and environmental factors is of importance in determining the health-adverse effects of VCM exposure.

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“…20 A significant negative interaction was observed between GSTT1 null and lung cancer in occupationally exposed subjects. 12 Speculations as to the mechanism of the protective effect of GSTT1 in human cancer have largely focused on the possibility that the products of GSTT1 conjugating reactions could produce in certain instances more carcinogenic metabolites, such as for the dihalomethanes and other chlorinated hydrocarbons, [21][22][23][24] which are known to be bioactivated by GSTT1. In addition, since the GST genes use certain chemopreventive compounds such as isothiocyanates as substrates, the deletion of GSTT1 could lead to the availability of higher levels of cancer preventing compounds.…”

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Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans

Garte

Taioli

Popov

et al. 2007

Intl Journal of Cancer

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A useful approach for studies on the mechanisms of genetic variation in cancer susceptibility is to use intermediary biochemical endpoints with mechanistic relevance to the genes under study. We examined the effects of individual genotype at seven metabolic gene loci on a marker of oxidative DNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine, in people exposed to polycyclic aromatic hydrocarbons (PAH) from three Central European cities. The GSTT1 homozygous deletion variant was associated with a significant protective effect for exposure to total PAHs and to eight specific PAHs, although the magnitude and significance of the effect varied among these compounds. Categorical sensitivity analysis was used to determine that the frequency of the GSTT1 deletion was significantly higher in people who proved to be more resistant to the DNA damaging effects of PAH exposure than in people who were the most sensitive. There is a growing literature on the protective effect of GSTT1 deletion in both disease and intermediary endpoints related to environmental carcinogenesis. The mechanism for this effect might be related to specific PAH substrate specificities, or could be related to other functions of GSTT1 gene in oxidative stress induced damage pathways. ' 2007 Wiley-Liss, Inc.Key words: biological markers; susceptibility; cohort studyThe paradigm of gene-environment interactions in carcinogenesis holds that genetic variation in loci responsible for the metabolism of carcinogens should be reflected in the well known variability in risk of cancer among exposed populations. This principle has been confirmed in some instances, but not in others, 1-4 mostly using case control approaches. One of the most studied metabolic gene families in this context is the glutathione-S-transferases (GST), which code for a family of phase II conjugating enzymes, generally considered to be involved in detoxification. 5,6 Since many classical electrophilic carcinogens are substrates for the GST enzymes, it has generally been hypothesized that the common human polymorphic variants of these genes, which for GSTM1 and GSTT1 are homozygous deletions, should result in a decrease in conjugation and subsequent elimination of carcinogenic intermediates, with the result of increasing the dose of carcinogen to target tissue. Individual case control studies, as well as pooled and meta analyses have confirmed this hypothesis to some extent, so that for example the deletion of GSTM1 variant was found to be associated with various cancer types, both alone and in combination with other genetic polymorphisms. 7-10 Careful analysis of the literature reveals a much more murky picture for the GSTT1 gene than for GSTM1. Although one group reported GSTT1 to be a risk factor for lung cancer, 11 the majority of studies have found no association between GSTT1 deletion and cancer as shown by a meta and pooled analysis, 12 and in general there are more negative findings for this variant than for the GSTM1 deletion. Even more interesting is the growing body of evidence that ...

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Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Cited by 179 publications

References 38 publications

DNA Polymerase I Is Essential for Growth of Methylobacterium dichloromethanicum DM4 with Dichloromethane

DNA Polymerase I Is Essential for Growth of Methylobacterium dichloromethanicum DM4 with Dichloromethane

Glutathione S-transferase M1 and GST T1 genetic polymorphisms and Raynaud’s phenomenon in French vinyl chloride monomer-exposed workers

Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans

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