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Expression patterns and novel splicing variants of glutathione-S-transferase isoenzymes of human lung and hepatocyte cell lines

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Abstract

Polymorphic glutathione S-transferase (GST) enzymes are involved in the metabolism of xenobiotics. They are of particular interest when studying disease susceptibility and adverse drug responses. The present work deals with the genetic polymorphisms and expression of the five GST classes (alpha, mu, pi, theta and zeta) in human lung and hepatocyte cell lines. We have determined their bioavailability for in vitro approaches. Common genetic polymorphisms of GSTM1 (*0, null), GSTT1 (*0) and GSTP1 (*A/*B, I105V) are detectable. The frequencies of the polymorphisms are within the expected range for a Caucasian population with one exception. The GSTM1*0 allele is 1.5-fold more frequent in lung cell lines. GST mRNAs are frequently but not uniformly distributed among unstimulated in vitro conditions. Lung cell lines show an approximately six-fold higher total GST transcript expression than hepatocyte cell lines. Additional GST transcripts have been identified for GSTT1; they represent alternative new splicing variants that occur in cancerous cell lines and in healthy lung tissue and blood. GST enzyme activity is mainly influenced by GSTP1. The activity promoted by 1-chloro-2,4-dinitrobenzene is significantly correlated to the GSTP1 mRNA expression level (R2=0.77, P<0.001). Individual human cell lines thus express GST isoenzymes in a similar pattern to human tissue. The most common genetic polymorphisms are present among the cell lines and have to be considered for in vitro stimulation approaches in a combinatory pattern.

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References

  • Aden DP, Fogel A, Plotkin S, Damjanov I, Knowles BB (1979) Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature 282:615–616

    Article  PubMed  CAS  Google Scholar 

  • Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J (1997) Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 272:10004–10012

    Article  CAS  Google Scholar 

  • Asahi Y, Kubonishi I, Imamura J, Kamioka M, Matsushita H, Furihata M, Ohtsuki Y, Miyoshi I (1996) Establishment of a clonal cell line producing granulocyte colony-stimulating factor and parathyroid hormone-related protein from a lung cancer patient with leukocytosis and hypercalcemia. Jpn J Cancer Res 87:451–458

    CAS  Google Scholar 

  • Ates NA, Tamer L, Ates C, Ercan B, Elipek T, Ocal K, Camdeviren H (2005) Glutathione S-transferase M1, T1, P1 genotypes and risk for development of colorectal cancer. Biochem Genet 43:149–163

    Article  PubMed  CAS  Google Scholar 

  • Autrup H (2000) Genetic polymorphisms in human xenobiotica metabolising enzymes as susceptibility factors in toxic response. Mut Res 464:65–76

    CAS  Google Scholar 

  • Bepler G, Koehler A, Kiefer P, Havemann K, Beisenherz K, Jaques G, Gropp C, Haeder M (1988) Characterization of the state of differentiation of six newly established human non-small-cell lung cancer cell lines. Differentiation 37:158–171

    Article  PubMed  CAS  Google Scholar 

  • Brower M, Carney DN, Oie HK, Gazdar AF, Minna JD (1986) Growth of cell lines and clinical specimens of human non-small cell lung cancer in a serum-free defined medium. Cancer Res 46:798–806

    PubMed  CAS  Google Scholar 

  • Comstock KE, Widersten M, Hao XY, Henner WD, Mannervik B (1994) A comparison of the enzymatic and physicochemical properties of human glutathione transferase M4-4 and three other human mu class enzymes. Arch Biochem Biophys 311:487–495

    Article  PubMed  CAS  Google Scholar 

  • Crawford EL, Khuder SA, Durham SJ, Frampton M, Utell M, Thilly WG (2000) Normal bronchial epithelial cell expression of glutathione transferase P1, glutathione transferase M3, and glutathione peroxidase is low in subjects with bronchogenic carcinoma. Cancer Res 60:1609–1618

    PubMed  CAS  Google Scholar 

  • Doney AS, Lee S, Leese GP, Morris AD, Palmer CN (2005) Increased cardiovascular morbidity and mortality in type 2 diabetes is associated with the glutathione S transferase theta-null genotype: a Go-DARTS study. Circulation 111:2927–2934

    Article  PubMed  CAS  Google Scholar 

  • Ellison M, Woodhouse D, Hillyard C, Dowsett M, Coombes RC, Gilby ED, Greenberg PB, Neville AM (1975) Immunoreactive calcitonin production by human lung carcinoma cells in culture. Br J Cancer 32:373–379

    PubMed  CAS  Google Scholar 

  • Falany CN (1997) Enzymology of human cytosolic sulfotransferases. FASEB J 11:206–216

    PubMed  CAS  Google Scholar 

  • Flamant C, Henrion-Caude A, Boelle PY, Bremont F, Brouard J, Delaisi B, Duhamel JF, Marguet C, Roussey M, Miesch MC, Boule M, Strange RC, Clement A (2004) Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis. Pharmacogenetics 14:295–301

    Article  PubMed  CAS  Google Scholar 

  • Fryer AA, Bianco A, Hepple M, Jones PW, Strange RC, Spiteri MA (2000) Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Am J Resp Crit Care Med 161:1437–1442

    PubMed  CAS  Google Scholar 

  • Gaspar P, Moreira J, Kvitko K, Torres M, Moreira A, Weimer T (2004) Cyp1A1, Cyp2E1, GSTM1, GSTT1, GSTP1, and TP53 polymorphisms: do they indicate susceptibility to chronic obstructive pulmonary disease and non-small-cell lung cancer? Genet Mol Biol 27:133–138

    Article  CAS  Google Scholar 

  • Gawronska-Szklarz B, Wojcicki M, Kuprianowicz A, Kedzierska K, Kedzierski M, Gornik W, Pawlik A (1999) CYP2D6 and GSTM1 genotypes in a Polish population. Eur J Clin Pharmacol 55:389–392

    Article  PubMed  CAS  Google Scholar 

  • Gazdar AF, Linnoila RI, Kurita Y, Oie HK, Mulshine JL, Clark JC, Whitsett JA (1990) Peripheral airway cell differentiation in human lung cancer cell lines. Cancer Res 50:5481–5487

    PubMed  CAS  Google Scholar 

  • Glatt H (2000) Sulfotransferases in the bioactivation of xenobiotics. Chem Biol Interact 129:141–170

    Article  PubMed  CAS  Google Scholar 

  • Guy CA, Hoogendoorn B, Smith SK, Coleman S, Donovan MC, Buckland PR (2004) Promoter polymorphisms in glutathione-S-transferase genes affect transcription. Pharmacogenetics 14:45–51

    Article  PubMed  CAS  Google Scholar 

  • Harries LW, Stubbins MJ, Forman D, Howard GC, Wolf CR (1997) Identification of genetic polymorphisms at the glutathione S-transferase pi locus and association with susceptibility to bladder, testicular and protate cancer. Carcinogenesis 18:641–644

    Article  PubMed  CAS  Google Scholar 

  • Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61:154–166

    Article  PubMed  CAS  Google Scholar 

  • Heidtmann HH, Salge U, Havemann K, Kirschke H, Wiederanders B (1993) Secretion of a latent, acid activatable cathepsin L precursor by human non-small cell lung cancer cell lines. Oncol Res 5:441–451

    PubMed  CAS  Google Scholar 

  • Henrion-Caude A, Flamant C, Roussey M, Housset C, Flahault A, Fryer AA, Chadelat K, Strange RC, Clement A (2002) Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology 36:913–917

    PubMed  CAS  Google Scholar 

  • Indulski JA, Lutz W (2000) Metabolic genotype in relation to individual susceptibility to environmental carcinogens. Int Arch Occup Environ Health 73:71–85

    Article  PubMed  CAS  Google Scholar 

  • Inskip A, Elexperu-Camiruaga J, Buxton N, Dias PS, MacIntosh J, Campbell D, Jones PW, Yengi L, Talbot JA, Strange RC, Fryer AA (1995) Identification of polymorphism at the glutathione S-transferase, GSTM3 locus: evidence for linkage with GSTM1*A. Biochem J 312:713–716

    PubMed  CAS  Google Scholar 

  • Ji X, Blaszczyk J, Xiao B, O’Donnell R, Hu X, Herzog C, Singh SV, Zimniak P (1999) Structure and function of residue 104 and water molecules in the xenobiotic substrate-binding site in human glutathione S-transferase P1-1. Biochemistry 38:10231–10238

    Article  PubMed  CAS  Google Scholar 

  • Ladero JM, Martinez C, Garcia-Martin E, Fernandez-Arquero M, Lopez-Alonso G, Concha EG de la, Diaz-Rubio M, Agundez JA (2005) Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease. Scand J Gastroenterol 40:348–353

    Article  PubMed  CAS  Google Scholar 

  • Lee YL, Hsiue TR, Lee YC, Lin YC, Guo YL (2005) The association between glutathione s-transferase p1, m1 polymorphisms and asthma in Taiwanese schoolchildren. Chest 128:1156–1162

    Article  PubMed  CAS  Google Scholar 

  • Lieber M, Smith B, Szakal A, Nelson-Rees W, Todaro G (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer 17:62–70

    Article  PubMed  CAS  Google Scholar 

  • Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD (1983) Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306:194–196

    Article  PubMed  CAS  Google Scholar 

  • Lu XM, Zhang YM, Lin RY, Arzi G, Wang X, Zhang YL, Zhang Y, Wang Y, Wen H (2005) Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh’s esophageal squamous cell cancer in Xinjiang, China. World J Gastroenterol 11:3651–3654

    PubMed  CAS  Google Scholar 

  • Mann CL, Davies MB, Boggild MD, Alldersea J, Fryer AA, Jones PW (2000) Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 54:552–557

    PubMed  CAS  Google Scholar 

  • Mannervik B, Danielson UH (1988) Glutathione transferases—structure and catalytic activity. CRC Crit Rev Biochem 23:283–337

    Article  PubMed  CAS  Google Scholar 

  • Mattey DL, Hassell AB, Plant M, Dawes PT, Ollier WR, Jones PW (1999) Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope. Ann Rheum Dis 58:164–168

    Article  PubMed  CAS  Google Scholar 

  • Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG (1998) Parkinson’s disease, pesticides, and glutathione transferase polymorphisms. Lancet 352:1344–1346

    Article  PubMed  CAS  Google Scholar 

  • Nakajima T, Elovaara E, Anttila S, Hirvonen A, Camus AM, Hayes JD, Ketterer B, Vainio H (1995) Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. Carcinogenesis 16:707–711

    Article  PubMed  CAS  Google Scholar 

  • Olshan AF, Weissler MC, Watson MA, Bell DA (2000) GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 9:185–191

    PubMed  CAS  Google Scholar 

  • Piipari R, Nurminen T, Savela K, Hirvonen A, Mantyla T, Anttila S (2003) Glutathion S-transferases and aromatic DNA adducts in smoker’s bronchoalveolar macrophages. Lung Cancer 39:265–272

    Article  PubMed  Google Scholar 

  • Raimondi S, Boffetta P, Anttila S, Brockmoller J, Butkiewicz D, Cascorbi I, Clapper ML, Dragani TA, Garte S, Gsur A, Haidinger G, Hirvonen A, Ingelman-Sundberg M, Kalina I, Lan Q, Leoni VP, Marchand LL, London SJ, Neri M, Povey AC, Rannug A, Reszka E, Ryberg D, Risch A, Romkes M, Ruano-Ravina A, Schoket B, Spinola M, Sugimura H, Wu X, Taioli E (2005) Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res [Epub ahead of print]

  • Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6:733–743

    PubMed  CAS  Google Scholar 

  • Sharma S, Nemecz SK, Zhu S, Stelle VE (1997) Identification of chemopreventive agents by screening for induction of glutathione-S-transferase as a biomarker. Methods Cell Sci 19:49–52

    Article  Google Scholar 

  • Spurdle AB, Webb PM, Purdie DM, Chen X, Green A, Chenevix-Trench G (2001) Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype. Carcinogenesis 22:67–72

    Article  PubMed  CAS  Google Scholar 

  • Srivastava DS, Mishra DK, Mandhani A, Mittal B, Kumar A, Mittal RD (2005) Association of genetic polymorphism of glutathione S-transferase M1, T1, P1 and susceptibility to bladder cancer. Eur Urol 48:339–344

    Article  PubMed  CAS  Google Scholar 

  • Stanulla M, Schrappe M, Brechlin AM, Zimmermann M, Welte K (2000) Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study. Blood 95:1222–1228

    PubMed  CAS  Google Scholar 

  • Sundberg K, Johansson AS, Stenberg G, Widersten M, Seidel A, Mannervik B, Jernström B (1998) Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons. Carcinogenesis 19:433–436

    Article  PubMed  CAS  Google Scholar 

  • Takaki T (1980) An epithelial cell line (KNS-62) derived from a brain metastasis of bronchial squamous cell carcinoma. J Cancer Res Clin Oncol 96:27–33

    Article  PubMed  CAS  Google Scholar 

  • Thier R, Taylor JB, Pemble SE, Humphreys WG, Persmark M, Ketterer B, Guengerich FP (1993) Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes. Proc Natl Acad Sci USA 90:8576–8580

    Article  PubMed  CAS  Google Scholar 

  • Turner AM, Zsebo KM, Martin F, Jacobsen FW, Bennett LG, Broudy VC (1992) Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood 80:374–381

    PubMed  CAS  Google Scholar 

  • Yun BR, El-Sohemy A, Cornelis MC, Bae SC(2005) Glutathione S-transferase M1, T1, and P1 genotypes and rheumatoid arthritis. J Rheumatol 32:992–997

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Human Exposure Research and Epidemiology, UFZ - Centre for Environmental Research Leipzig-Halle, Permoserstrasse 15, 04318, Leipzig, Germany

    Mario Bauer, Olf Herbarth, Anja Dotzauer, Carolin Graebsch & Eike Schmuecking

  2. Research Laboratories, Department of Surgery, University of Leipzig, Leipzig, Germany

    Gabriela Aust

  3. Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany

    Jan G. Hengstler

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  1. Mario Bauer
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  2. Olf Herbarth
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Correspondence to Mario Bauer.

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Bauer, M., Herbarth, O., Aust, G. et al. Expression patterns and novel splicing variants of glutathione-S-transferase isoenzymes of human lung and hepatocyte cell lines. Cell Tissue Res 324, 423–432 (2006). https://doi.org/10.1007/s00441-005-0150-8

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  • DOI: https://doi.org/10.1007/s00441-005-0150-8

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