Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis.

Ferroptosis is an iron-dependent mode of cell death caused by excessive oxidative damage to lipids. Lipid peroxidation is normally suppressed by glutathione peroxidase 4, which requires reduced glutathione. Cystine is a major resource for glutathione synthesis, especially in cancer cells. Therefore, cystine deprivation or inhibition of cystine uptake promotes ferroptosis in cancer cells. However, the roles of other molecules involved in cysteine deprivation-induced ferroptosis are unexplored. We report here that the expression of gamma-glutamyltransferase 1 (GGT1), an enzyme that cleaves extracellular glutathione, determines the sensitivity of glioblastoma cells to cystine deprivation-induced ferroptosis at high cell density (HD). In glioblastoma cells expressing GGT1, pharmacological inhibition or deletion of GGT1 suppressed the cell density-induced increase in intracellular glutathione levels and cell viability under cystine deprivation, which were restored by the addition of cysteinylglycine, the GGT product of glutathione cleavage. On the other hand, cystine deprivation induced glutathione depletion and ferroptosis in GGT1-deficient glioblastoma cells even at an HD. Exogenous expression of GGT1 in GGT1-deficient glioblastoma cells inhibited cystine deprivation-induced glutathione depletion and ferroptosis at an HD. This suggests that GGT1 plays an important role in glioblastoma cell survival under cystine-limited and HD conditions. We conclude that combining GGT inhibitors with ferroptosis inducers may provide an effective therapeutic approach for treating glioblastoma.

Effects of H3 and H4 histones acetylation and bindings of CREB binding protein and p300 at the promoter on hepatic expression of gamma-glutamyltransferase gene in a streptozotocin-induced moderate hypoinsulinemic rat model.

Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency. However, the mechanism of hepatic Ggt regulation has not been explored fully. In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression of Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model. The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats. Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats. These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.

Serum Exosomal Gamma-Glutamyltransferase Activity Increased in Patients with Renal Cell Carcinoma with Advanced Clinicopathological Features.

BACKGROUND: There has been no clinically useful diagnostic or prognostic biomarker for renal cell carcinoma (RCC). Serum γ-glutamyltransferase (GGT) activity has been reported to be a prognostic marker for several types of cancer including RCC. Exosomes or small extracellular vesicles present in body fluids have potential as a biomarker. We have recently demonstrated that GGT activity on exosomes isolated from serum is useful for the differential diagnosis of prostate cancer and benign prostate hyperplasia. In this study, we aimed to examine if serum exosomal GGT activity could be a marker for RCC. METHODS: We examined GGT1 expression and GGT activity in cell lysates and exosomes from culture medium of HK-2 proximal tubule epithelial and RCC cell lines. GGT activity was measured using a fluorescent probe for GGT, γ-glutamyl hydroxymethyl rhodamine green. Serum and serum exosomal GGT activities were measured in patients with RCC. GGT1 expression in RCC tissues was evaluated by immunohistochemical staining. RESULTS: GGT1 levels in exosomes from KMRC-1, OS-RC-2 and 786-O cells were elevated compared with those from HK-2 cells. In exosomes, GGT1 expression correlated with GGT activity determined using a fluorescent probe for GGT. In RCC patients, serum exosomal GGT activity was elevated in those with advanced stages (III/IV vs. I/II, p = 0.037) and those with microvascular invasion (with vs. without, p = 0.034). Immunohistochemical analysis showed that membranous GGT1 expression was increased in RCC with microvascular invasion. Notably, preoperative serum exosomal GGT activity could predict the likelihood of having microvascular invasion diagnosed by pathological examination of surgically resected specimens. CONCLUSIONS: Our results suggest that serum exosomal GGT activity could be a clinically useful marker for advanced clinicopathological features of RCC patients, and its combined use with conventional diagnostic modalities may improve the diagnosis and treatment of patients.

The value of neutrophil to lymphocyte ratio and gamma-glutamyl transpeptidase to platelet ratio in patients with hepatocellular carcinoma.

Our study aimed to evaluate the value of neutrophil to lymphocyte ratio (NLR) and gamma-glutamyl transpeptidase to platelet ratio (GPR) in patients with hepatocellular carcinoma (HCC).A total of 565 patients with pathological diagnosis of HCC were retrospectively analyzed and 414 patients diagnosed with cirrhosis were treated as a control group. All clinical materials were collected from the First Affiliated Hospital of Guangxi Medical University.The preintervention NLR, GPR, and α-fetoprotein (AFP) were significantly higher in HCC patients than in the controls (PNLR < .000, PGPR < .000, PAFP < .000). The NLR and GPR were correlated with the Barcelona clinic liver cancer (BCLC) stages, Child-Pugh grades, and tumor size, but not with Edmondson-Steiner grades. Combined use of NLR or GPR with AFP produced larger area under the curve (AUC) (AUCNLR+AFP = 0.916; AUCNLR+AFP = 0.953) than NLR (P < .000), GPR (P < .000), or AFP (P < .000) used alone.The preintervention hematologic parameters (NLR and GPR) studied herein were associated with the BCLC stages of HCC. Combined use of NLR or GPR with AFP may improve early detection and diagnosis of HCC.

High level extracellular production of recombinant γ-glutamyl transpeptidase from Bacillus licheniformis in Escherichia coli fed-batch culture.

Increasing demand of microbial γ-glutamyl transpeptidase (GGT) in food and pharmaceutical sectors raised the need for process development for high level production of the enzyme. In this respect, GGT from Bacillus licheniformis ER15 (SBLGGT) was cloned along with its native secretion signal and expressed in E. coli using different expression vectors. Native signal of the enzyme assistedits extracellular translocationin E. coli.Maximum enzyme expression was shown by construct pET51b-sblggt,in comparison to other clones, in E. coli. Shake-flask cultivation and expression using Luria-Bertani (LB) medium resulted in 2800 U/l enzyme titers in 48 h which was furtherenhancedto 4.3-fold after optimizing various cultivation conditions viz. inducer concentration, agitation, medium and induction optical density. High cell density cultivation using fed-batch fermentation strategy resulted in 20-fold increase over shake flask studies to a level of 61250 U/l. After 24 h,the specific product yield was 2355 U/g dry cell weight (DCW)with volumetric productivity of 2552 U/l/h. Of the total enzyme expressed,40% was translocated extracellularly during high cell density fed-batch fermentation resulting in an enzyme activity of 24500 U/l in the extracellular medium after 24 h. This is the highest reported enzyme titers of bacterial GGT enzyme in E. coli expression system. Thus, the current study provides a cost-effective method for the over-expression and preparation of bacterial GGT enzyme for its industrial applications.

Reduced Hepatocellular Expression of Canalicular Transport Proteins in Infants with Neonatal Cholestasis and Congenital Hypopituitarism.

OBJECTIVE: To assess whether prolonged neonatal cholestasis, described in congenital hypopituitarism and septo-optic dysplasia (SOD), is associated with altered expression of selected canalicular ectoenzymes and canalicular transport proteins. STUDY DESIGN: Children with congenital hypopituitarism (n = 21), SOD (n = 18), and cholestasis seen in our center over 26 years were reviewed. Histopathologic findings in archival liver biopsy specimens were assessed (n = 10) and in those with low/normal levels of serum γ-glutamyltransferase (GGT) activity despite conjugated hyperbilirubinemia, expression of canalicular ectoenzymes and canalicular transport proteins was evaluated immunohistochemically. RESULTS: Patients presented at a median age of 8 weeks (range 3-20 weeks) with median total bilirubin 116 µmol/L (45-287 µmol/L), GGT 95 IU/L (25-707 UI/L), and serum cortisol 51 nmol/L (17-240 nmol/L). All but 3 had low free thyroxin (median 9.6 pmol/L [6.8-26.9]) with increased thyroid-stimulating hormone levels (median 5.95 mU/L [<0.1-9.24]). Liver histologic features included moderate-to-severe intralobular cholestasis with nonspecific hepatitis, giant-cell transformation of hepatocytes, and fibrosis. In all, immunohistochemical staining for canalicular ectoenzymes and canalicular transport proteins revealed a degree of reduced expression, associated with normal serum GGT values in 6 of the 10 patients, and another 6 nonbiopsied infants with cholestasis also had low/normal serum GGT activity. Sequencing of ABCB11 and ATP8B1 performed in 6 of the biopsied patients did not identify pathogenic mutations. Following replacement therapy, biochemical evidence of hepatobiliary injury resolved in all children within a median period of 6 months. CONCLUSION: Hepatobiliary involvement in congenital hypopituitarism associated with SOD has a good prognosis, but its etiology remains uncertain. Immunohistochemical expression of canalicular transport proteins was reduced in available liver samples.

High Resolution X-ray Diffraction Dataset for Bacillus licheniformis Gamma Glutamyl Transpeptidase-acivicin complex: SUMO-Tag Renders High Expression and Solubility.

Gamma glutamyl transpeptidase, (GGT) is a ubiquitous protein which plays a central role in glutathione metabolism and has myriad clinical implications. It has been shown to be a virulence factor for pathogenic bacteria, inhibition of which results in reduced colonization potential. However, existing inhibitors are effective but toxic and therefore search is on for novel inhibitors, which makes it imperative to understand the interactions of various inhibitors with the protein in substantial detail. High resolution structures of protein bound to different inhibitors can serve this purpose. Gamma glutamyl transpeptidase from Bacillus licheniformis is one of the model systems that have been used to understand the structure-function correlation of the protein. The structures of the native protein (PDB code 4OTT), of its complex with glutamate (PDB code 4OTU) and that of its precursor mimic (PDB code 4Y23) are available, although at moderate/low resolution. In the present study, we are reporting the preliminary analysis of, high resolution X-ray diffraction data collected for the co-crystals of B. licheniformis, Gamma glutamyl transpeptidase, with its inhibitor, Acivicin. Crystals belong to the orthorhombic space group P212121 and diffract X-ray to 1.45 Å resolution. This is the highest resolution data reported for all GGT structures available till now. The use of SUMO fused expression system enhanced yield of the target protein in the soluble fraction, facilitating recovery of protein with high purity. The preliminary analysis of this data set shows clear density for the inhibitor, acivicin, in the protein active site.

Hyperproduction of γ-glutamyl transpeptidase from Bacillus licheniformis ER15 in the presence of high salt concentration.

BACKGROUND: Microbial γ-glutamyl transpeptidases (GGTs) have been exploited in biotechnological, pharmaceutical, and food sectors for the synthesis of various γ-glutamyl compounds. But, till date, no bacterial GGTs are commercially available in the market because of lower levels of production from various sources. In the current study, production of GGT from Bacillus licheniformis ER15 was investigated to achieve high GGT titers. RESULTS: Hyperproduction of GGT from B. licheniformis ER15 was achieved with 6.4-fold enhancement (7921.2 ± 198.7 U/L) by optimization of culture medium following one-variable-at-a-time strategy and statistical approaches. Medium consisting of Na2HPO4: 0.32% (w/v); KH2PO4: 0.15% (w/v); starch: 0.1% (w/v); soybean meal: 0.5% (w/v); NaCl: 4.0% (w/v), and MgCl2: 5 mM was found to be optimal for maximum GGT titers. Maximum GGT titers were obtained, in the optimized medium at 37°C and 200 rpm, after 40 h. It was noteworthy that GGT production was a linear function of sodium chloride concentration, as observed during response surface methodology. While investigating the role of NaCl on GGT production, it was found that NaCl drastically decreased subtilisin concentration and indirectly increasing GGT recovery. CONCLUSION: B. licheniformis ER15 is proved to be a potential candidate for large-scale production of GGT enzyme and its commercialization.

Effect of the three-dimensional organization of liver cells on the biogenesis of the γ-glutamyltransferase fraction pattern.

Context Four gamma-glutamyltransferase (GGT) fractions with different molecular weights (big-, medium-, small- and free-GGT) are detectable in human plasma. Objective Verify if liver cells can release all four GGT fractions and if the spatial cell organization influences their release. Methods Hepatoma (HepG2) and melanoma (Me665/2/60) cells were cultured as monolayers or spheroids. GGT released in culture media was analysed by gel-filtration chromatography. Results HepG2 and Me665/2/60 monolayers released the b-GGT fraction, while significative levels of s-GGT and f-GGT were detectable only in media of HepG2-spheroids. Bile acids alone or in combination with papain promoted the conversion of b-GGT in s-GGT or f-GGT, respectively. Conclusions GGT is usually released as b-GGT, while s-GGT and f-GGT are likely to be produced in the liver extracellular environment by the combined action of bile acids and proteases.

Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC.

Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether à-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying γ-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN-treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials.

Proteomic analysis of enzyme production by Bacillus licheniformis using different feather wastes as the sole fermentation media.

This study evaluates the use of different types of feathers as fermentation media for enzyme production. Bacillus licheniformis was grown on the feathers, which lead to total biodegradation due to bacterial enzymatic hydrolytic excretion. B. licheniformis excretes protease and lipase activity, with feather concentration being the main parameter controlling their generation. Using a proteomic approach, the proteins excreted during fermentation were identified, and the influence of the chemical composition of the feathers on protein secretion was tested. The identified proteins are hydrolytic enzymes such as keratinase, gamma-glutamyltranspeptidase, chitosanases, and glicosidases. The diversity of proteins is related to the chemical complexity of the feathers. Understanding the composition of a hydrolytic system, when B. licheniformis is cultured on different feathers, may assist in utilizing such a system for producing different hydrolytic enzymes. The data indicate that proteomics can be a valuable tool for describing the physiological state of B. licheniformis cell populations growing on different wastes.

Combined incubation of colon carcinoma cells with phorbol ester and mitochondrial uncoupling agents results in synergic elevated reactive oxygen species levels and increased γ-glutamyltransferase expression.

The NADPH oxidase (NOX) is a significant determinant for the expression and activity of γ-glutamyltransferase (GGT), which is frequently upregulated after increased levels of reactive oxygen species (ROS) and oxidative stress. Earlier studies on human colon carcinoma HT-29 cells have shown that treatment with phorbol 12-myristate 13-acetate (PMA) activates NOX thus increasing the intracellular level of ROS and upregulating GGT. Another important source of cellular ROS is the mitochondria, and treatment with the mitochondria uncoupler carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone (FCCP) results in increased ROS levels. The present study shows that when HT-29 cells were simultaneously treated with both agents, a significant and synergic increase in intracellular ROS was detected. NOX activity contributed at least 50 % of this increase as inhibiting NOX activity with apocynin or downregulating the NOX activity using siRNA against p22 phox reduced the synergic ROS production. The combined FCCP and PMA treatment also provoked highly increased GGT mRNA levels after 24 h whereas only minor and delayed increases in GGT protein and enzyme activity levels were detected. The results strongly indicate that ROS production by both mitochondria and NOX is involved in the regulation of GGT expression in colon carcinoma cells.

Mechanisms of intracellular defense and activity of free radical oxidation in rat myocardium in the dynamics of chronic fluorine intoxication.

The mechanisms of intracellular defense and activity of free radical oxidation in the myocardium were studied in the dynamics of chronic fluorine intoxication. At the early stages of fluorine intoxication (day 3-week 3), the concentrations of defense proteins HIF-1α, HSC73, and HOx-2 and activity of the main metabolic enzymes increased, which promoted maintenance of cardiomyocyte structure and function at the normal physiological level. At late stages of fluorine intoxication (weeks 6 and 9), metabolic changes in the myocardium attest to high strain of the adaptive mechanisms.

Glutamine-induced production and secretion of Helicobacter pylori gamma-glutamyltranspeptidase at low pH and its putative role in glutathione transport.

Helicobacter pylori increased the gamma-glutamyltranspeptidase (GGT) production under low-pH (maximal at pH 4) and appropriate pCO2 conditions, while the production of GGT mRNA correlated with increased total enzyme activity. At pH 4, the bacterium augmented enzyme production in the presence of glutamine (~10 mM) in the medium, which predominantly occurred after a 6-min time-lag. Monovalent salts such as NaCl or NH4Cl facilitated enzymatic activation in acidic solutions of approximately pH 4.5. In addition, glutathione's gamma-glutamyl moiety cysteinylglycine appeared to be taken up readily by the intact H. pylori, but not by the one pretreated with a potent GGT inhibitor, acivicin, suggesting that the GGT may partake in glutathione uptake by the cell.

Compartment- and malignance-dependent up-regulation of γ-glutamyltranspeptidase and dipetidylpeptidase-IV activity in human brain gliomas.

γ-Glutamyltranspeptidase (GGT, syn. γ-Glutamyltransferase) and dipeptidylpeptidase-IV (DPP-IV) activity participates in metabolic and growth control of normal and tumor cells by processing biologically active peptides. Here, we report on up-regulation of these enzymes in human brain gliomas determined by catalytic enzyme histochemistry and immunocytochemistry. Higher activity of GGT was found in 50%, 68% and 81% of WHO grade II, III and IV tumors, respectively. The process started at/near the microvasculature, from where it spread to the parenchyma. On average, the enzyme activity in grade II, III and IV gliomas exceeded controls 2.0, 3.0 and 3.5-fold, respectively. Up-regulation of DPP-IV-like activity also started at the microvasculature, but mainly in pericytes and mononuclear-like cells around the vessels and dispersed in the parenchyma. Marked elevation of this enzyme activity, comprising also tumor parenchyma, occurred only in grade IV glioblastomas (65% patients; 3.6 times above controls) which can, therefore, help in their differentiation from grade III gliomas. The increase of total DPP-IV-like activity also included its two enzymatic homologs, the canonical DPP-IV/CD26 and FAP-1α. The increase in GGT is supposed to be a tumor grade dependent response of microvasculature and tumor astrocytes to stress induced by tissue hypoxia and/or the metabolic aberrancies. The increase in DPP-IV-like activity in high-grade tumors can be attributed to inflammatory/scavenging processes performed by the mononuclear-like cells and, in glioblastomas, also to regressive changes in the structure and function of the microvasculature and tumor parenchyma, including astrocyte stress response. The inverse relationship between DPP-IV-like activity and Ki67 in most glioblastomas and shorter survival time of patients with low activity of this enzyme also suggest its anti-oncogenic effects.

Effects of pH and dissolved oxygen on the synthesis of γ-glutamyltranspeptidase from Bacillus subtilis SK 11.004.

BACKGROUND: γ-Glutamyltranspeptidase (GGT; EC 2.3.2.2) is a widely distributed enzyme that is of interest in the food industry. In this study the effects of pH and dissolved oxygen (DO) on GGT synthesis from Bacillus subtilis SK 11.004 were investigated. RESULTS: GGT production increased to 0.5 U mL⁻¹ when the pH value was controlled at 6.5. The control of a single DO level revealed that the highest specific growth rate (3.42 h⁻¹) and GGT production rate (0.40 U g⁻¹ mL⁻¹) were obtained at DO levels of 40 and 10% respectively. To satisfy the different oxygen demands at different stages of cell growth and GGT synthesis, a stage DO level control strategy was designed as follows: 40% from 0 to 4 h, 30% from 4 to 6 h and 10% from 6 to 18 h. Furthermore, the maximum biomass (2.27 g L⁻¹) and GGT production (3.05 U mL⁻¹) could be obtained using a fermentation strategy combining a constant pH value with stage DO level control. CONCLUSION: The proposed fermentation strategy resulted in a 13.7-fold increase in GGT production. This finding should be of great importance for the industrial production of GGT.

Alanine aminotransferase decreases with age: the Rancho Bernardo Study.

BACKGROUND: Serum alanine aminotransferase (ALT) is a marker of liver injury. The 2005 American Gastroenterology Association Future Trends Committee report states that serum ALT levels remain constant with age. This study examines the association between serum ALT and age in a community-dwelling cohort in the United States. METHODS: A cross-sectional study of 2,364 (54% female) participants aged 30-93 years from the Rancho Bernardo Study cohort who attended a research clinic visit in 1984-87. Demographic, metabolic co-variates, ALT, bilirubin, gamma glutamyl transferase (GGT), albumin, and adiposity signaling biomarkers (leptin, IL-6, adiponectin, ghrelin) were measured. Participants were divided into four-groups based upon age quartile, and multivariable-adjusted least squares of means (LSM) were examined (p for trend <0.05). RESULTS: ALT decreased with increasing age, with mean ALT levels (IU/L) of 23, 21, 20, and 17 for those between quartile ages 30-62, 63-71, 72-77, and 78-93 years (p<0.0001). Trends of decreasing LSM ALT with age and the decreasing prevalence of categorically defined elevated serum ALT with age remained robust after adjusting for sex, alcohol use, metabolic syndrome components, and biomarkers of adiposity (p-value <0.0001), and was not materially changed after adjusting for bilirubin, GGT, and albumin. CONCLUSIONS: ALT levels decrease with age in both men and women independent of metabolic syndrome components, adiposity signaling biomarkers, and other commonly used liver function tests. Further studies are needed to understand the mechanisms responsible for a decline in ALT with age, and to establish the optimal cut-point of normal ALT in the elderly.

Gamma-glutamyltransferase of cancer cells at the crossroads of tumor progression, drug resistance and drug targeting.

Gamma-glutamyltransferase (GGT) is a key enzyme involved in glutathione metabolism and whose expression is often significantly increased in human malignancies. In the past years, several studies focused on the possible role of GGT in tumor progression, invasion and drug resistance. The involvement of a pro-oxidant activity of GGT, besides its early recognized contributions to cellular antioxidant defenses, has been repeatedly documented. GGT-derived pro-oxidants can modulate important redox-sensitive processes and functions of the cell, with particular reference to its proliferative/apoptotic balance, which has obvious and important implications in tumor progression and drug resistance. In addition, the specificity of the enzymatic reaction carried out by GGT suggests that suitable pro-drugs could be selectively metabolized (activated) by GGT expressed in tumor tissue. This paper is a review of the recent investigation in the field, focusing on the potential role of GGT as a diagnostic/prognostic marker, as well as a target for anticancer treatments.

Association of gamma-glutamyltransferase with incidence of type 2 diabetes in Japan.

The aim of this research was to examine the association of gamma-glutamyltransferase (GGT) and its interactions with alcohol consumption (alcohol), body mass index (BMI) and/or alanine aminotransferase (ALT) on the incidence of type 2 diabetes (DM) in Japan. Data from annual health examinations obtained from 1995 to 2005 were analyzed. The total number of subjects in this cohort was 39,563. Hazard ratios (HRs) were calculated by Cox regression analysis. GGT levels were positively associated with the incidence of DM in both men and women, after adjustment for several variables, including alcohol, BMI and ALT. Among women, the association was stronger in non-drinkers than in drinkers due to a significant interaction of GGT and alcohol. In non-drinkers, the HRs of the third and fourth GGT quartiles in women and the fourth GGT quartile in men were significantly higher than those of the first GGT quartile. The association between BMI and the incidence of DM was enhanced by increased GGT levels in women. When GGT levels were in the second to fourth quartiles, the HRs of obese subjects were significantly higher than those of underweight subjects. Conversely, obesity was no longer a significant risk factor for DM when GGT level was in the first quartile. Increased GGT levels were associated with the development of DM after adjustment for several possible confounding factors. The association between GGT and DM in non-drinkers was significantly stronger than that in drinkers. Furthermore, in women, obesity is no longer a risk factor for DM when GGT level is low.

Redox regulation of gamma-glutamyl transpeptidase.

gamma-Glutamyl transpeptidase (GGT) catalyzes the transfer of the glutamyl moiety from glutathione, and glutathione S-conjugates to acceptors to form another amide or to water to produce free glutamate. Functionally, GGT plays important roles in glutathione homeostasis and mercapturic acid metabolism. The expression of GGT is increased as an adaptive response upon the exposure of oxidative stress. The underlying mechanism of this, however, is nebulous, as GGT gene structure is complex and its transcription is usually controlled by multiple promoters that generate several subtypes of GGT mRNAs. Studies reveal that signaling pathways such as Ras, ERK, p38MAPK, and PI3K are involved in the induction of GGT gene expression in response to oxidative stress. Thus, not surprisingly, induction of GGT mRNA subtypes and the involvement of multiple signaling pathways vary depending on cell type and stimuli.