Structural distinction of rat GSH transferase subunit 10

Meyer, David J.; Gilmore, K S; Coles, Brian; Dalton, Kaye G.; Hulbert, Peter B.; Ketterer, B.

doi:10.1042/bj2740619a

Cited by 25 publications

(8 citation statements)

References 7 publications

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“…CHB and CHBSG. Recently the primary sequence of the murine alpha GST subunit (mYc) was obtained by Beutler and Eaton (1992) and it is clearly more closely related to the rat liver GST subunit 10 (Meyer et al, 1991b) and/or Yc2 (Hayes et al, 1991) rather than the major rat alpha GST subunits la, lb and 2. GST subunit 10 occurs mainly in foetal and neonatal rat liver (Tee et al, 1992) and may also be induced in adult liver by 1,2-dithiole-3-thione or ethoxyquin (Hayes et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases

Meyer

Gilmore²,

Harris³

et al. 1992

Br J Cancer

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Summary The spontaneous reaction of 110 ILM chlorambucil (4-[p-[bis(2-chloroethyl) However, GTSs Al-I and A2-2 were associated with a significant increase of CHBSG at the expense of CHBSG2 + CHBSGOH suggesting that these GTSs sequestered CHBSG at the active site. This interpretation was supported by inhibition studies which showed that CHBSG was a pure competitive inhibitor of the activity of GSTs Al-l and A2-2 towards 1-chloro-2,4-dinitrobenzene with Ki's of 1.3 and 1.2 tiM respectively. GSH transferases P1-1 and Mla-la were inhibited by CHBSG above 10 LM.Incubation of 2 tLM CHB, a concentration which may be of more significance for chemotherapy, in the presence or absence of GST A 1-2 (20-50 LM) showed catalysis of GSH monoconjugation equivalent to 18% of the spontaneous rate. However, the dominant effect again was the sequestration of CHBSG which reached 74.3 ± 1.5 (SEM)% of the total reactants at 60 min compared to 28.9 ± 0.3(SEM)% in controls. CHBSG, although possessing a potential electrophilic centre, showed no detectable alkylation of plasmid DNA but indirect evidence was obtained that it alkylated other cellular macromolecules.It is concluded that the contribution of GSTs to catalysis of CHB detoxication will depend on factors not previously considered, namely the relative molarities of CHB, CHBSG and GSTs, and the cellular capacity to excrete CHBSG to relieve product inhibition. CHB is a hydrophobic anion at physiological pH and was shown by Bank et al. (1989) to enter and leave leukaemic lymphocytes rapidly by simple diffusion. In plasma, CHB is stabilised by binding to albumin (Ehrsson et al., 1981).A major problem in the use of cancer chemotherapeutics is the development of cellular resistance and, in the case of alkylating agents such as CHB, numerous studies suggest that enhanced expression of glutathione transferases (GSTs) may contribute to such resistance. For instance: Lewis et al. (1988) found that amplification of an alpha class GST in a Chinese hamster ovary (CHO) cell line was associated with resistance to CHB and other nitrogen mustards; Puchalski and Fahl (1990) found increased resistance to CHB upon transfection of mouse and monkey cells with rat GSTs 1-1 (class alpha), 3-3 (class mu) or human GST P1-1 (class pi, for nomenclature of human GSTs see Mannervik et al., 1992), and Johnston et al. (1990) found an inverse correlation between both GSH and total GST activity and CHB-dependent DNA adducts formed in vitro in human chronic lymphocytic leukaemic lymphocytes. In support of these observations, murine GSTs of alpha, mu and pi classes were shown by Ciaccio et al. (1990) to increase significantly the rate of formation of CHBSG in vitro at pH 6.5, and the alpha class enzyme also stimulated the second GSH conjugation. Recently, Ciaccio et al. (1991) have also observed catalysis of the GSH conjugaton of CHB by human GSTs of the alpha and pi classes. In contrast, the transfection of GST P1-I into NIH 3T3 cells failed to alter their sensitivity to CHB (Nakagawa et al., 1990). Moreover, L...

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Section: Discussionmentioning

confidence: 99%

Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases

Meyer

Gilmore²,

Harris³

et al. 1992

Br J Cancer

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“…The GSTs also form a superfamily. 133,134 The major isoforms, which involve the metabolic activation of carcinogens derived from tobacco smoke or the detoxification of the respective activated carcinogens, are GSTM1, GSTM3, GSTT1, and GSTP1. Other Phase II enzymes are EPHX1, NQO1, N-acetyltransferases (NATs), UDPglucuronosyltransferase, aldehyde dehydrogenase, sulfotransferase, and superoxide dismutase.…”

Section: Genetic Epidemiologymentioning

confidence: 99%

NQO1, MPO, and the risk of lung cancer: A HuGE review

Kiyohara

Yoshimasu

Takayama

et al. 2005

Genetics in Medicine

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The aim of this study is to summarize the available molecular epidemiologic studies of lung cancer and metabolic genes, such as NAD(P)H quinone reductase 1 (NQO1) and myeloperoxidase (MPO). NQO1 plays a dual role in the detoxification and activation of procarcinogens whereas MPO has Phase I activity by converting lipophilic carcinogens into hydrophilic forms. Variant genotypes of both NQO1 Pro187 Ser and MPO G-463A polymorphisms may be related to low enzyme activity. The Pro/Ser and Ser/Ser genotypes combined of NQO1 was significantly associated with decreased risk of lung cancer in Japanese [random effects odds ratio (OR) ϭ 0.70, 95% confidence interval (CI) ϭ 0.56--0.88] among whom the variant allele is common. The variant genotype of MPO was associated with decreased risk of lung cancer among Caucasians (random effects OR ϭ 0.70, 95% CI ϭ 0.47--1.04). Gene-environment interactions in both polymorphisms may be hampered by inaccurate categorization of tobacco exposure. Evidence on gene-gene interactions is extremely limited. As lung cancer is a multifactorial disease, an improved understanding of such interactions may help identify individuals at risk for developing lung cancer. Such a study should include larger sample size and other polymorphisms in the metabolism of tobaccoderived carcinogens and address interactions with smoking status. The effects of polymorphisms are best represented by their haplotypes. In future studies on lung cancer, the development of haplotype-based approaches will facilitate the evaluation of haplotypic effects, either for selected polymorphisms physically close to each other or for multiple genes within the same drug-metabolism pathway. Genet Med 2005:7(7):463-478.Key Words: lung cancer, NAD(P)H quinone oxidoreductase 1 polymorphism, myeloperoxidase polymorphism, molecular epidemiology, meta-analysis GENES NAD(P)H quinone reductase 1 NAD(P)H quinone oxidoreductase 1 (NQO1, EC 1.6.99.2), formerly referred to as DT-diaphorase, is an important flavoprotein that catalyzes the two-electron reduction of carcinogenic quinoid compounds into their reduced form, such as hydroquinones. 1 Benzo(a)pyrene (BP) is one of the most important carcinogens, and the formation of BP quinone-DNA adduct is prevented by NQO1. 2 In contrast, carcinogenic heterocyclic amines present in smoke are metabolically activated by NQO1. 3 Therefore, this enzyme is thought to be involved in both metabolic activation and detoxification of carcinogens. Higher levels of tissue (cytoplasm) expression of the NQO1 have been detected in the lung, kidney, liver, and skeletal muscle, with lower levels in the heart, brain, and placenta. 4 Myeloperoxidase Myeloperoxidase (MPO, EC 1.11.1.7) is a lysosomal hemoprotein located in the azurophilic granules of polymorphonuclear leukocytes and monocytes. MPO is the most abundant protein in neutrophils, constituting approximately 5% of their dry weight. 5 MPO has Phase I metabolizing activity by converting lipophilic carcinogens into hydrophilic forms. 6 Exposure to a variety of pulmon...

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“…The separation and quantification of GST subunits was carried out according to Vandenberghe et al (1990), using an LC10 system (Shimadzu, Berelux, 's-Hertogen-bosch, Netherlands) with a Prolinea 4/33 HPLC-dedicated integrator (Compaq, Houston, TX, USA). The GST subunits were identified by comparison of the retention time obtained for the individual peaks with those of purified GST subunits and by comparison of the patterns generated with characteristic extrahepatic GST profiles and previously published GST HPLC profiles (Hiratsuka et al 1990, Vandenberghe et al 1990, Meyer et al 1991, Johnson et al 1990, 1993, Kispert et al 1989, Meyer et al 1989. GST subunits were quantified using peak areas of the respective subunits from HPLC, together with molecular masses (Mannervik & Danielson 1988) and molar extinction coefficients at 214 nm, as given by Johnson et al (1992).…”

Section: Isolation and Separation Of Gst Subunitsmentioning

confidence: 99%

“…Several aspects of both endogenous and exogenous hepatic GST regulation have been mainly studied in vivo (McLellan & Hayes 1987, Scott & Kirsh 1987, Li & Tu 1989, Meyer et al 1991, 1993, Singhal et al 1992a,b, Hatayama et al 1993. It is, however, generally agreed that it is difficult to make a distinction between the direct and indirect effects of hormones and drugs administered in vivo.…”

Section: Introductionmentioning

confidence: 99%

Hormonal regulation of glutathione S-transferase expression in co-cultured adult rat hepatocytes

Coecke¹,

Vanhaecke²,

Foriers³

et al. 2000

Journal of Endocrinology

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Glutathione S-transferases (GSTs) are subject to regulation by thyroid and sex hormones and by GH. We have used an in vitro experimental system comprising adult rat hepatocytes co-cultured with rat liver epithelial cells of primitive biliary origin, to distinguish between direct and indirect effects of various hormones on GSTs; to identify the GST subunits affected by individual hormones; and to investigate the level at which the hormones act. Triiodothyronine (T 3 ), thyroxine (T 4 ) and 17 -oestradiol (OE 2 ) reduced GST activities, whereas testosterone, dihydrotestosterone, and human growth hormone (hGH) had little effect on total GST activity. HPLC separation of the various GST subunits revealed that T 3 and T 4 reduced total GST content, in particular the abundance of subunits M1 and M2. The amount of the Pi-class subunit P1 was reduced by OE 2 . Treatment of the co-cultured cells with this hormone altered the GST subunit profile to one that is more similar to that observed in freshly isolated hepatocytes. Analysis of mRNAs demonstrated that some of the hormones act at a pre-translational level, whereas others act at a translational or post-translational level to regulate the expression of various GST subunits.

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Structural distinction of rat GSH transferase subunit 10

Cited by 25 publications

References 7 publications

Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases

Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases

NQO1, MPO, and the risk of lung cancer: A HuGE review

Hormonal regulation of glutathione S-transferase expression in co-cultured adult rat hepatocytes

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