Abstract
Since early after the introduction of serum γ-glutamyltransferase (GGT) in clinical practice as a reliable and widely employed laboratory test, epidemiological and prospective studies have repeatedly shown that this activity possesses a prognostic value for morbidity and mortality. The association is independent of possibly concomitant conditions of liver disease, and notably, a significant independent correlation of serum GGT exists with the occurrence of cardiovascular diseases (myocardial infarction, stroke). Experimental work has documented that active GGT is present in atherosclerotic plaques of coronary as well as in cerebral arteries. These findings, and the recently recognized functions of GGT in the generation of reactive oxygen species, indicate that serum GGT represents a true marker of cardiovascular diseases and underlying atherosclerosis. Further insights into potential therapeutic interest will probably be derived from studies investigating the origin of GGT activity in plaque tissue.
References
1 Forman HJ, Liu R-M, Tian L. Glutathione cycling in oxidative stress. Lung Biol Health Dis 1997; 105:99–121.Search in Google Scholar
2 Hanigan MH, Frierson HF. Immunohistochemical detection of γ-glutamyl transpeptidase in normal human tissue. J Histochem Cytochem 1996; 44:1101–8.10.1177/44.10.8813074Search in Google Scholar
3 Maellaro E, Dominici S, Del Bello B, Valentini MA, Pieri L, Perego P, et al. Membrane γ-glutamyl transpeptidase activity of melanoma cells: effects on cellular H2O2 production, cell surface protein thiol oxidation and NF-κB activation status. J Cell Sci 2000; 113:2671–8.10.1242/jcs.113.15.2671Search in Google Scholar
4 Taniguchi N, Iizuka S, Zhe ZN, House S, Yokosawa N, Ono M, et al. Measurement of human serum immunoreactive γ-glutamyl transpeptidase in patients with malignant tumors using enzyme-linked immunosorbent assay. Cancer Res 1985; 45:5835–9.Search in Google Scholar
5 Rajpert-De Meyts E, Shi M, Chang M, Robison TW, Groffen J, Heisterkamp N, et al. Transfection with γ-glutamyl transpeptidase enhances recovery from glutathione depletion using extracellular glutathione. Toxicol Appl Pharmacol 1992; 114:56–62.10.1016/0041-008X(92)90096-BSearch in Google Scholar
6 Shi M, Gozal E, Choy HA, Forman HJ. Extracellular glutathione and γ-glutamyl transpeptidase prevent H2O2-induced injury by 2,3-dimethoxy-1,4-naphthoquinone. Free Radic Biol Med 1993; 15:57–67.10.1016/0891-5849(93)90125-ESearch in Google Scholar
7 Liu RM, Shi MM, Giulivi C, Forman HJ. Quinones increase γ-glutamyl transpeptidase expression by multiple mechanisms in rat lung epithelial cells. Am J Physiol 1998; 274:L330–6.10.1152/ajplung.1998.274.3.L330Search in Google Scholar PubMed
8 Kugelman A, Choy HA, Liu R, Shi MM, Gozal E, Forman HJ. γ-Glutamyl transpeptidase is increased by oxidative stress in rat alveolar L2 epithelial cells. Am J Respir Cell Mol Biol 1994; 11:586–92.10.1165/ajrcmb.11.5.7946387Search in Google Scholar PubMed
9 Chang M, Shi M, Forman HJ. Exogenous glutathione protects endothelial cells from menadione toxicity. Am J Physiol 1992; 6:L634–7.10.1152/ajplung.1992.262.5.L637Search in Google Scholar PubMed
10 Takahashi Y, Oakes SM, Williams MC, Takahashi S, Miura T, Joyce-Brady M. Nitrogen dioxide exposure activates γ-glutamyl transferase gene expression in rat lung. Toxicol Appl Pharmacol 1997; 143:388–96.10.1006/taap.1996.8087Search in Google Scholar PubMed
11 Hybertson BM, Lee YM, Cho HG, Cho OJ, Repine JE. Alveolar type II cell abnormalities and peroxide formation in lungs of rats given IL-1 intratracheally. Inflammation 2000; 24:289–303.10.1023/A:1007092529261Search in Google Scholar
12 Knickelbein RG, Ingbar DH, Seres T, Snow K, Johnston RB Jr, Fayemi O, et al. Hyperoxia enhances expression of γ-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung. Am J Physiol 1996; 14:L115–22.10.1152/ajplung.1996.270.1.L115Search in Google Scholar PubMed
13 Kappus H, Sies H. Toxic drug effects associated with oxygen metabolism: redox cycling and lipid peroxidation. Experientia 1981; 37:1233–41.10.1007/BF01948335Search in Google Scholar
14 Stark A-A, Zeiger E, Pagano DA. Glutathione metabolism by γ-glutamyl transpeptidase leads to lipid peroxidation: characterization of the system and relevance to hepatocarcinogenesis. Carcinogenesis 1993; 14:183–9.10.1093/carcin/14.2.183Search in Google Scholar
15 Dominici S, Paolicchi A, Lorenzini E, Maellaro E, Comporti M, Pieri L, et al. γ-Glutamyltransferase-dependent prooxidant reactions: a factor in multiple processes. BioFactors 2003; 17:187–98.10.1002/biof.5520170118Search in Google Scholar
16 Del Bello B, Paolicchi A, Comporti M, Pompella A, Maellaro E. Hydrogen peroxide produced during γ-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells. FASEB J 1999; 13:69–79.10.1096/fasebj.13.1.69Search in Google Scholar
17 Paolicchi A, Dominici S, Pieri L, Maellaro E, Pompella A. Glutathione catabolism as a signalling mechanism. Biochem Pharmacol 2002; 64:1029–37.10.1016/S0006-2952(02)01173-5Search in Google Scholar
18 Lee DH, Gross MD, Jacobs DR Jr. Association of serum carotenoids and tocopherols with γ-glutamyltransferase: the Cardiovascular Risk Development in Young Adults (CARDIA) Study. Clin Chem 2004; 50:582–8.10.1373/clinchem.2003.028852Search in Google Scholar PubMed
19 Lee DH, Steffen LM, Jacobs DR Jr. Association between serum γ-glutamyltransferase and dietary factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr 2004; 79:600–5.10.1093/ajcn/79.4.600Search in Google Scholar PubMed
20 Corti A, Raggi C, Franzini M, Paolicchi A, Pompella A, Casini AF. Plasma membrane γ-glutamyltransferase activity facilitates the uptake of vitamin C in melanoma cells. Free Radic Biol Med 2004. In press.10.1016/j.freeradbiomed.2004.08.015Search in Google Scholar PubMed
21 Lee DH, Jacobs DR Jr, Gross M, Kiefe CI, Roseman J, Lewis CE, et al. γ-Glutamyltransferase is a predictor of incident diabetes and hypertension. Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem 2003; 49:1358–66.10.1373/49.8.1358Search in Google Scholar PubMed
22 Lee DH, Blomhoff R, Jacobs DR. Is serum γ-glutamyltransferase a marker of oxidative stress? Free Radic Res 2004; 38:535–9.10.1080/10715760410001694026Search in Google Scholar PubMed
23 Niida S, Kawahara M, Ishizuka Y, Ikeda Y, Kondo T, Hibi T, et al. γ-Glutamyltranspeptidase stimulates receptor activator of nuclear factor-kappa B ligand expression independent of its enzymatic activity and serves as a pathological bone-resorbing factor. J Biol Chem 2004; 279:5752–6.10.1074/jbc.M311905200Search in Google Scholar
24 Bibas M, Zampa G, Procopio A, Guaitolini R. High serum γ-glutamyltransferase concentrations in a family. N Engl J Med 1994; 330:1832–3.10.1056/NEJM199406233302518Search in Google Scholar
25 Whitfield JB, Zhu G, Nestler JE, Heath AC, Martin NG. Genetic covariation between serum γ-glutamyltransferase activity and cardiovascular risk factors. Clin Chem 2002; 48:1426–31.10.1093/clinchem/48.9.1426Search in Google Scholar
26 Bathum L, Petersen HC, Rosholm J-U, Bathum L, Petersen HC, Rosholm JU, et al. Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem 2001; 47:81–7.10.1093/clinchem/47.1.81Search in Google Scholar
27 Kristenson H, Ohrn J, Trell E, Hood B. Serum γ-glutamyltransferase at screening and retrospective sickness days. Lancet 1980; 1:1141.10.1016/S0140-6736(80)91593-7Search in Google Scholar
28 Peterson B, Trell E, Kristensson H, Fex G, Yettra M, Hood B. Comparison of γ-glutamyltransferase and other health screening tests in average middle-aged males, heavy drinkers and alcohol non-users. Scand J Clin Lab Invest 1983; 43:141–9.10.3109/00365518309168236Search in Google Scholar
29 Conigrave KM, Saunders JB, Reznik RB, Whitfield JB. Prediction of alcohol-related harm by laboratory test results. Clin Chem 1993; 39:2266–70.10.1093/clinchem/39.11.2266Search in Google Scholar
30 Brenner H, Rothenbacher D, Arndt V, Schuberth S, Fraisse E, Fliedner TM. Distribution, determinants, and prognostic value of γ-glutamyltranspeptidase for all-cause mortality in a cohort of construction workers from south Germany. Prev Med 1997; 26:305–10.10.1006/pmed.1997.0144Search in Google Scholar PubMed
31 Arndt V, Brenner H, Rothenbacher D, Zschenderlein B, Fraisse E, Fliedner TM. Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality. Int Arch Occup Environ Health 1998; 71:405–12.10.1007/s004200050299Search in Google Scholar PubMed
32 Karlson BW, Wiklund O, Hallfren P, Sjolin M, Lindquist J, Herlitz J. Ten-year mortality among patients with a very small or unconfirmed acute myocardial infarction in relation to clinical history, metabolic screening and signs of myocardial ischemia. J Intern Med 2000; 247:449–56.10.1046/j.1365-2796.2000.00679.xSearch in Google Scholar PubMed
33 Betro MG, Oon RC, Edwards JB. γ-Glutamyl transpeptidase and other liver function tests in myocardial infarction and heart failure. Am J Clin Pathol 1973; 60:679–83.10.1093/ajcp/60.5.679Search in Google Scholar
34 Hood B, Kjellstrom T, Ruter G, Kristenson H. Serum cholesterol, serum triglyceride, alcohol, myocardial infarction and death (2): necessary to pay attention to serum GT in assessment of risks of myocardial infarction and death. Lakartidningen 1990; 87:3295–8.Search in Google Scholar
35 Wannamethee G, Ebrahim S, Shaper AG. γ-Glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995; 142:699–708.10.1093/oxfordjournals.aje.a117699Search in Google Scholar
36 Jousilahti P, Rastenyte D, Tuomilehto J. Serum γ-glutamyltransferase, self-reported alcohol drinking, and the risk of stroke. Stroke 2000; 31:1851–5.10.1161/01.STR.31.8.1851Search in Google Scholar
37 Bots ML, Salonen JT, Elwood PC, Nikitin Y, Freire de Concalves A, Inzitari D, et al. γ-Glutamyltransferase and risk of stroke: the EUROSTROKE project. J Epidemiol Community Health 2002; 56(Suppl 1):2529.10.1136/jech.56.suppl_1.i25Search in Google Scholar
38 van Barneveld T, Seidell JC, Traag N, Hautvast JG. Fat distribution and γ-glutamyl transferase in relation to serum lipids and blood pressure in 38-year old Dutch males. Eur J Clin Nutr 1989; 43:809–18.Search in Google Scholar
39 Nilssen O, Førde OH, Brenn T. The Tromsø Study – distribution and population determinants of γ-glutamyltransferase. Am J Epidemiol 1990; 132:318–26.10.1093/oxfordjournals.aje.a115661Search in Google Scholar
40 Daeppen JB, Smith TL, Schuckit MA. Influence of age and body mass index on γ-glutamyltransferase activity: a 15-year follow-up evaluation in a community sample. Alcohol Clin Exp Res 1998; 22:941–4.10.1097/00000374-199806000-00027Search in Google Scholar
41 Yamada Y, Ishizaki M, Kido T, Honda R, Tsuritani I, Yamaya H. Relationship between serum γ-glutamyl transpeptidase activity and blood pressure in middle-aged male and female non-drinkers. J Hum Hypertens 1990; 4:609–14.Search in Google Scholar
42 Miura K, Nakagawa H, Nakamura H, Tabata M, Nagase H, Yoshida M, et al. Serum γ-glutamyl transferase level in predicting hypertension among male drinkers. J Hum Hypertens 1994; 8:445–9.Search in Google Scholar
43 Yamada Y, Ikai E, Tsuritani I, Ishizaki M, Honda R, Ishida M. The relationship between serum γ-glutamyl transpeptidase levels and hypertension: common in drinkers and nondrinkers. Hypertens Res 1995; 18:295–301.10.1291/hypres.18.295Search in Google Scholar
44 Umeki S, Hisamoto N, Hara Y. Study on background factors associated with impaired glucose tolerance and/or diabetes mellitus. Acta Endocrinol (Copenh) 1989; 120:729–34.10.1530/acta.0.1200729Search in Google Scholar
45 Rantala AO, Lilja M, Kauma H, Savolainen MJ, Reunanen A, Kesaniemi YA. γ-Glutamyl transpeptidase and the metabolic syndrome. J Intern Med 2000; 248:230–8.10.1046/j.1365-2796.2000.00723.xSearch in Google Scholar
46 Colloredo-Mels G, Bettale G, Bellati G, Guanziroli M, Bertone V, Angeli G, et al. γ-Glutamyl-transpeptidase in diabetics: a case control study. Clin Chim Acta 1988; 175:189–95.10.1016/0009-8981(88)90009-5Search in Google Scholar
47 Perry IJ, Wannamethee SG, Shaper AG. Prospective study of serum γ-glutamyltransferase and risk of NIDDM. Diabetes Care 1998; 21:732–7.10.2337/diacare.21.5.732Search in Google Scholar
48 Emdin M, Passino C, Michelassi C, Titta F, L’Abbate A, Donato L, et al. Prognostic value of serum γ-glutamyl transferase activity after myocardial infarction. Eur Heart J 2001; 22:1802–7.10.1053/euhj.2001.2807Search in Google Scholar
49 Amoroso G, Van Boven AJ, Crijns HJ. Drug therapy or coronary angioplasty for the treatment of coronary artery disease: new insights. Am Heart J 2001; 141:S22–5.10.1067/mhj.2001.109945Search in Google Scholar
50 Jousilahti P, Vartiainen E, Alho H, Poikolainen K, Sillanaukee P. Opposite associations of carbohydrate-deficient transferrin and γ-glutamyltransferase with prevalent coronary heart disease. Arch Intern Med 2002; 162:817–21.10.1001/archinte.162.7.817Search in Google Scholar
51 Wuyts B, Delanghe JR. The analysis of carbohydrate-deficient transferrin, marker of chronic alcoholism, using capillary electrophoresis. Clin Chem Lab Med 2003; 41:739–46.10.1515/CCLM.2003.113Search in Google Scholar
52 Muntwyler J, Hennekens CH, Buring JE, Gaziano JM. Mortality and light to moderate alcohol consumption after myocardial infarction. Lancet 1998; 352:1882–5.10.1016/S0140-6736(98)06351-XSearch in Google Scholar
53 Berliner JA, Heinecke JW. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 1996; 20:707–27.10.1016/0891-5849(95)02173-6Search in Google Scholar
54 Paolicchi A, Minotti G, Tonarelli P, Tongiani R, De Cesare D, Mezzetti A, et al. γ-Glutamyl transpeptidase-dependent iron reduction and low density lipoprotein oxidation – a potential mechanism in atherosclerosis. J Invest Med 1999; 47:151–60.Search in Google Scholar
55 Spear N, Aust SD, Thiol-mediated NTA-Fe(III) reduction and lipid peroxidation. Arch Biochem Biophys 1994; 312:198–202.10.1006/abbi.1994.1299Search in Google Scholar PubMed
56 Paolicchi A, Emdin E, Ghliozeni E, Ciancia E, Passino C, Popoff G, et al. Atherosclerotic plaques contain γ-glutamyl transpeptidase activity. Circulation 2004; 109:1440.10.1161/01.CIR.0000120558.41356.E6Search in Google Scholar PubMed
57 Emdin M, Passino M, Donato L, Paolicchi A, Pompella A. Serum γ-glutamyltransferase as a risk factor of ischemic stroke might be independent of alcohol consumption. Stroke 2002; 33:1163–4.10.1161/01.STR.0000012344.35312.13Search in Google Scholar
58 Bauvois B, Laouar A, Rouillard D, Wietzerbin J. Inhibition of γ-glutamyl transpeptidase activity at the surface of human myeloid cells is correlated with macrophage maturation and transforming growth factor β production. Cell Growth Differ 1995; 6:1163–70.Search in Google Scholar
59 Watanabe M, Taketa K, Izumi M, Nagashima H. Association of γ-glutamyltransferase with plasma lipoprotein and lipid-protein complex in cholestasis. Hepatogastroenterology 1984; 31:204–7.Search in Google Scholar
60 Huseby NE. Multiple forms of serum γ-glutamyltransferase. Association of the enzyme with lipoproteins. Clin Chim Acta 1982; 124:103–12.10.1016/0009-8981(82)90324-2Search in Google Scholar
61 Artur Y, Wellman-Bednawska M, Jacquier A, Siest G. Associations between serum γ-glutamyltransferase and apolipoproteins: relationships with hepatobiliary diseases. Clin Chem 1984; 30:1318–21.10.1093/clinchem/30.8.1318Search in Google Scholar
62 Castaldo G, Intrieri M, Castellano L, de Sio I, Del Vecchio Blanco C, Sacchetti L, et al. Serum γ-glutamyltransferase isoform complexed to LDL in the diagnosis of small hepatocellular carcinoma. Clin Chem 1999; 45:1100–2.10.1093/clinchem/45.7.1100aSearch in Google Scholar
63 Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci 2001; 38:263–355.10.1080/20014091084227Search in Google Scholar PubMed
64 Nyström E, Bengtsson C, Lindstedt G, Lapidus L, Lindquist O, Waldenström J. Serum γ-glutamyl transferase in a Swedish female population. Age-related reference intervals; morbidity, and prognosis in cases with raised catalytic concentrations. Acta Med Scand 1988; 224:79–84.10.1111/j.0954-6820.1988.tb16741.xSearch in Google Scholar
65 Whitfield JB, Zhu G, Heath AC, Powell LW, Martin NG. Effects of alcohol consumption on indices of iron stores, and of iron stores on alcohol intake markers. Alcohol Clin Exp Res 2001; 25:1037–45.10.1111/j.1530-0277.2001.tb02314.xSearch in Google Scholar
66 Arnesen E, Huseby NE, Brenn T, Try K. The Tromsø Heart Study: distribution of, and determinants for, γ-glutamyltransferase in a free-living population. Scand J Clin Lab Invest 1986; 46:63–70.10.3109/00365518609086483Search in Google Scholar PubMed
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