Increased GGT Activity Research Articles

Exploring porcine kidney explants as a model for the study of nephrotoxins and the therapeutic potential of phytic acid

The use of in vivo models to assess nephrotoxicity has faced ethical limitations. A viable alternative is the ex vivo model that combines the 3 R principles with the preservation of tissue histology. Here, we established a gentamicin nephrotoxicity model using pigs` kidney explants and investigated the effect of phytic acid (IP6) against gentamicin- induced nephrotoxicity. A total of 360 kidney explants were divided into control, gentamicin (10 mM), IP6 (5 mM), and gentamicin+IP6 groups. The activity of gammaglutamyltransferase (GGT), creatinine levels, histological assessment, oxidative stress, and inflammatory cytokine expression were analyzed. Exposure to gentamicin induced an increase in GGT activity, creatinine levels, lesion score, lipoperoxidation and IL-8 expression. Explants exposed to IP6 remained like the control. The addition of IP6 to gentamicin prevented tissue damage, increasing the antioxidant status and gene expression of IL-10. This model proved to be an adequate experimental approach for identifying nephrotoxins and potential products to modulate the toxicity.

ПОКАЗАТЕЛИ ФУНКЦИЙ ГЕПАТОБИЛИАРНОЙ СИСТЕМЫ У БОЛЬНЫХ ХРОНИЧЕСКИМ ОПИСТОРХОЗОМ С ГЕНЕТИЧЕСКОЙ ПРЕДРАСПОЛОЖЕННОСТЬЮ К РАЗВИТИЮ САХАРНОГО ДИАБЕТА 2 ТИПА

To assess the influence of genetic features of metabolic processes on the reactivity to opisthorchiasis invasion, biochemical parameters of the hepatobiliary system functions were studied in chronic opisthorchiasis patients with and without mutant alleles of polymorphisms associated with the type 2 diabetes mellitus. It was found that the presence of mutations in the genes PPARG and TCF7L2 (rs12255372), HHEX, IGF2BP2 and SLC30A8 enhances the opisthorchiasis negative impact on the activity of alpha-amylase and indicators of impaired bile secretion. The presence of a rare allele of the IGF2BP2 gene prevents an increase in GGT activity, and the presence of a rare allele of the CDKAL1 and SLC30A8 genes reduces the degree of increase in glucose concentration in opisthorchiasis. Key words: chronic opisthorchiasis, polymorphisms, type 2 diabetes mellitus, biochemical parameters, disorders of bile secretion.

Influence of first colostrum pasteurization on serum immunoglobulin G, iron, and activity of gamma-glutamyltransferase in newborn dairy calves.

Background and Aim:Colostrum pasteurization is an established procedure in dairy farms in developed countries. This practice can improve the health status of the offspring by reducing several pathogens. This study aimed to focus on the pasteurization of bovine first colostrum and its influence on certain important bioactive components.Materials and Methods:This study was conducted in Holstein-Friesian bull calves, which were randomly divided into two groups and fed with 6 L of untreated (UT, n=10) or 6 L of heat-treated (HT, 63.5°C for 30 min, n=10) colostrum from their own dam within the first 12 h after birth. Blood samples were taken before, 24 h, and 48 h after first colostrum intake to determine the concentrations of immunoglobulin G (IgG) and iron and the activity of gamma-glutamyltransferase (GGT) in the serum.Results:The level of IgG was not affected by pasteurization (p=0.19). However, a slower increase in GGT activity (p<0.05) and a lower serum iron concentration (p=0.04) were observed in the HT group.Conclusion:It can be concluded that pasteurization influences the absorption of colostrum components and therefore, the passive transfer of immunity, although the level of IgG was not affected by pasteurization in this study.

Increased risk of acute pancreatitis occurrence in smokers with rs5751901 polymorphisms in GGT1 gene.

Objectives: The study was aimed to assess γ‑glutamyltransferase (GGT) activity and concentration as a marker of oxidative stress induced by exposure to tobacco smoke in acute pancreatitis (AP) course. Examination of the relationship between GGT activity/concentration and single-nucleotide polymorphism (SNP rs5751901 and rs2236626) in GGT1 gene was performed.Subjects and methods: We examined SNPs in 38 AP patients and 51 healthy subjects by PCR-RFLP methods. GGT concentration in blood was measured with the use of the ELISA method; GGT activity and GSH concentration were measured by the Szasz and Patterson methods, respectively.Results: In the non-AP smokers group with TC genotype for SNPrs5751901 an increased blood GGT activity compared to smokers with CC genotypes was shown. In the course of AP was observed an elevated GGT activity and the value of GGT activity/GGT concentration ratio in smokers compared to non-smokers, in AP patients with TC genotypes and CC genotypes, respectively, for both SNP: rs5751901 and rs2236626. In the group of smoking AP patients with the CC and TC genotypes in rs5751901 locus and CC and TT genotypes in rs2236626 locus a decreases in GSH concentration during hospitalization were noted.Conclusions: SNP rs5751901 and rs2236626 cause changes in GGT activity. Smoking in the AP course contributes to increased GGT activity and excessive GSH use up in patients with TC and CC genotypes for both SNPs. Exposure to smoke xenobiotics enhances (3-fold) the risk of AP occurrence in individuals with TC genotypes for SNP rs5751901.

Функціональний стан нирок щурів за умов ацетамінофен-індукованого ушкодження на тлі аліментарної депривації протеїну

The article explores the functional state of kidneys in animals with acetaminophen-induced intoxication, which were maintained under the conditions of different protein supply. The research model involved the division of animals into next equal groups: group I – rats, which were maintained on a complete semi-synthetic diet; group II – rats, which were kept on a low-protein diet; ІІІ – rats with acetaminophen-induced injury, maintained on a complete semi-synthetic diet; IV – rats with acetaminophen-induced injury, which were previously kept on the low-protein diet. It was established, that kidney function of animals, which were maintained in conditions of the alimentary deprivation of protein, was characterized by the disturbances of the filtration capacity on the background of a slight decrease in reabsorption capacity. It is evidenced by a minor increase in GGT activity and urine Na+ level, along with significant proteinuria against the background of GFR reduction and preservation of plasma creatinine level. In animals with acetaminophen-induced injury, an increase in GGT activity, urine Na+ level and proteinuria in the absence of GFR and plasma creatinine changes, indicates the primary damage to renal tubular cells, while maintaining the filtration capacity of the kidney. The most significant changes in the filtration capacity of kidney were recorded in animals receiving toxic doses of acetaminophen on the background of alimentary deficiency of protein: a significant increase in plasma creatinine on the background of a 4-fold decrease in glomerular filtration. Proteinuria, increased γ-glutamyltransferase activity, and an increase in urine Na+ level indicates the damage to tubular cells and impaired renal reabsorption capacity. The conclusion was made, that lack of protein in the diet is a factor leading to a worsening of kidney dysfunction in animals with acetaminophen-induced intoxication since under those conditions disturbances of both filtration and reabsorption capacity of the kidney are observed.

The prevalence of elevated gamma-glutamyltransferase and sorbitol dehydrogenase activity in racing Thoroughbreds and their associations with viral infection.

In racehorses, serum gamma-glutamyltransferase (GGT) activity is positively correlated with cumulative days in training and, when ≥100IU/L, has been associated with poor performance. The prevalence of increased GGT activity in North American Thoroughbreds and its aetiopathogenesis are unknown. Four emerging viruses, pegivirus E (PgV E; equine pegivirus), hepacivirus A (HcV A; equine hepacivirus), pegivirus D (PgV D; Theiler's disease virus), and equine parvovirus-hepatitis (EqPV-H) have been identified in horses with clinical and subclinical hepatopathy. Available prevalence data indicate these viruses may commonly infect racehorses and contribute to increased liver enzyme activity in this population. To investigate the association between viral infection and increased liver enzyme activity in racing Thoroughbreds. Cross-sectional study. Prerace blood samples were collected from 802 Thoroughbreds and tested for GGT and sorbitol dehydrogenase (SDH) activity, and the presence of PgV E, HcV A, PgV D and EqPV-H nucleic acid. Increased SDH and/or GGT were detected in 56.2% of the 802 serum samples. The infection prevalence and relative risk (RR) of having concurrently increased liver enzyme activity were: PgV E=18.2% (RR=0.820, 95% CI=0.662-0.978, P=0.03), HcV A=2.5% (RR=1.132, 95% CI=0.719-1.466, P=0.6), PgV D=0.5% (RR=0.875, 95% CI=0.165-1.598, P>0.9), EqPV-H=2.9% (RR=0.916, 95% CI=0.564-1.266, P=0.7). Longitudinal samples were not tested. While viral infection was common among Thoroughbreds in this study, infection did not explain the high prevalence of increased liver enzyme activity. In fact, PgV E infection was associated with a reduced risk of having increased liver enzyme activity, indicating PgV E is unlikely to be a cause of hepatitis in horses. Importantly, like GGT, increased SDH activity was highly prevalent in this study, and provides additional evidence that hepatocellular injury was occurring in these horses.

Serum Gamma-Glutamyltransferase Levels are Associated with Cardiovascular Risk Factors in China: A Nationwide Population-Based Study

Serum gamma-glutamyltransferase (GGT), which is mainly derived from the liver, is a sensitive marker of liver cell damage and oxidative stress. More recently, it has been found that increased GGT plasma activity is also associated with cardiovascular disease (CVD). However, data on the relationship between GGT and cardiovascular risk factors (CRFs) are lacking in nationally representative samples of the Chinese population. Here, we aim to investigate both the association between GGT and CRFs and CRF clustering. A cross-sectional survey was conducted in a representative sample of 22897 adults aged 18 years and older from 2007 to 2011 nationally, which included a plurality of ethnic minorities. The participants were then divided into quartiles of sex-specific serum GGT. From the low to high GGT quartiles, the incidence of each CRF and clustered risk factors increased after adjusting for age, uric acid (UA), ethnicity, drinking, and all other risk factors. Individuals in the upper stratum (>75th percentile) had higher prevalence rates of CRFs than did those in the lower stratum (all P < 0.05). Furthermore, the subjects with clustering of 1, 2, or ≥3 CRFs were still more likely to belong to the upper GGT quartiles (75th percentiles) than were those without risk factors (all P < 0.05). In conclusion, our data highlight that there is an association between higher serum GGT levels and prevalence of CRFs, which tend to cluster with the increase in GGT activity in Chinese adults.

Surto de dermatofilose em bezerros Nelore criados extensivamente em Goiás

Background: Dermatophilosis is an infectious-contagious disease of acute, subacute or chronic evolution caused by the etiologic agent Dermatophilus congolensis, and presents as hyperplastic or exudative dermatitis with crusty and scaly skin eruptions. Although it is a disease with important economic impact on Brazilian beef cattle, the reports of outbreaks in zebu cattle are restricted to the states of São Paulo and Mato Grosso do Sul. The present paper aimed to report the epidemiological, clinical, laboratorial and pathological findings of a dermatophilosis outbreak in Nelore calves raised extensively in Goiás, Midwestern Brazil.Case: An outbreak of skin lesions in Nelore calves occurred on a farm located in Cocalzinho de Goiás, Goiás, Midwestern Brazil. Fifty one (25.5%) of the 200 calves from 3-11-months-old presented cutaneous lesions. Forty nine of the calves were still suckling and two were weaned recently, and the most affected calves were offspring’s of cows with the lowest body condition score. Three severely affected calves were clinically examined presenting regular body condition score, pale pink ocular mucosa, fever (39.2-40.3°C), tachycardia (80-100 beats per minute), tachypnea (48-56 breaths per minute) and moderate presence of ticks. Skin inspection revealed crusty, elevated, non-pruritic lesions of grayish color that easily detached from the skin exposing a humid and hemorrhagic superficial lesion with pus. Lesions were widespread on the body with predominance on the face, ears, neck and dorsal region. Hematological findings of these calves presented leukocytosis (16,083 ± 1,910/µL) by netrophilia (11,121 ± 2,349/µL) and hyperfibrinogenemia (966.6 ± 208.16 mg/dL). Biochemical alterations consisted of hypoproteinemia (6.5 ± 0.5 g/dL) and a slight increase in GGT activity in two calves (28 and 19 U/L, respectively). Skin lesions samples were stained by Giemsa and demonstrated filaments presenting characteristic “train tracks” pattern, formed by parallel chains of cocci. Microscopic findings consisted of suppurative superficial dermatitis associated with intralesional bacteria. Histological sections stained by Gram revealed typical branched filamentous structures formed by multiple rows of Gram positive spherical cocci. Initially, treatment consisted in improve the herd body condition score and ticks control. Calves were treated for dermatophilosis with streptomycin (25 mg.kg-1, s.i.d., intramuscularly [IM], four days) and chlorhexidine diglylate 2% baths with manual crusts removal. Due to relapse in most calves caused by sub dosages by the owner, long-acting oxytetracycline (20 mg.kg-1, q48 h, IM, three doses) and stable disinfection was recommended. One year after this outbreak, the owner stated that there were no new cases on the farm.Discussion: Definitive diagnosis of dermatophilosis in the calves of this report was conducted by the association of epidemiological, clinical, cytological and histological findings. In the present report, predisposing factors such as low body condition score due to food shortage, micro injuries on the skin caused by ticks infestation and mechanical trauma by Brachiaria brizantha, and high temperatures, possibly acted synergistically causing this outbreak. Dermatophilosis treatment with long-acting oxytetracycline associated with topical treatment and environment disinfection allowed clinical cure and prevention of new cases in this farm. Long-acting oxytetracycline presents good results in the treatment of natural cases of dermatophilosis, reaching cure rates varying from 71.4 to 100%. Outbreaks of dermatophilosis in Nelore calves in Goiás may cause significant losses in beef cattle productivity and measures of control and prophylaxis should be considered for prevention.

Liver-Specific Overexpression of Gamma-Glutamyltransferase Ameliorates Insulin Sensitivity of Male C57BL/6 Mice.

In the current study, we developed a liver-specific GGT-overexpressing mice model by rapid injection pLIVE-GGT vector through tail vein and investigated the effects of GGT elevation on glucose metabolism and insulin sensitivity. The serum GGT activity was significantly increased after 7 days of pLIVE-GGT1 vector delivery and lasted for about 3 weeks. GGT overexpression reduced the levels of GSSG and GSH in the liver and serum and had no effects on total antioxidative capacity in the liver, kidney, and skeletal muscle except for the pancreas. Increased GGT activity had no effect on the glucose tolerance but could facilitate blood glucose lowering after intraperitoneal insulin administration. The results of Western blotting showed that increased GGT activity enhanced insulin-induced AKT phosphorylation at Ser473. Furthermore, GGT inhibitor could attenuate the changes of insulin-induced blood glucose uptake and AKT phosphorylation in the liver. In summary, the present study developed a liver-specific GGT-overexpressing mice model and found that GGT elevation in short term had no effects on glucose metabolism but could increase insulin sensitivity through enhancing the activity of insulin signaling pathway.

1α,25-Dihydroxyvitamin D3 enhances γ-glutamyl transpeptidase activity in LLC-PK1 porcine kidney epithelial cells.

Mammalian γ-glutamyl transpeptidase (GGT) is expressed most highly in the kidney and serves to recover the constituent amino acids of glutathione in the proximal tubules. Serum GGT is used as a marker for obstructive jaundice and alcoholic liver disease and it has been reported that urinary GGT is a potential marker for bone resorption. The present study investigated the effect of derivatives of vitamin D3 on GGT activity in LLC-PK1 porcine renal tubular epithelial cells in order to analyze the biochemical basis of bone metabolism-associated alterations in GGT activity in the kidney. In the presence of 1α,25-dihydroxyvitamin D3 [1,25(OH)2VD3], GGT activity was observed to be significantly increased in LLC-PK1 cells, with an increase in GGT activity also found in the cell medium. While the stimulatory effect of 1-OH-VD3 was similar to that of 1,25(OH)2VD3, vitamin D3 and 25-OH-VD3 had no effect on GGT activity. The increased GGT activity caused by 1,25(OH)2VD3 in LLC-PK1 cells was the result of long-term stimulation of the cells, in contrast to the GGT-induced increase in alkaline phosphatase, which is more transient. Polymerase chain reaction analysis revealed that the 1,25(OH)2VD3‑induced increase in GGT activity was due to prolonged GGT turnover, rather than increased GGT expression, as no increase in GGT mRNA expression was observed. Thus, it is likely that the expression of GGT is not entirely constitutive in the kidney, but is altered under certain conditions, including under hormonal regulation.

Is γ-glutamyl Transferase Activity a Potential Marker of Left Ventricular Function During Early Postmyocardial Infarction period?

γ-glutamyl transferase (GGT) is an independent prognostic marker for cardiac death and reinfarction in patients with coronary artery disease, but its clinical significance during early postmyocardial infarction period is unclear. This short-term prospective study included 40 patients with acute myocardial infarction (AMI) in whom we determined GGT activity, lipids, uric acid, homocysteine (Hcy), high sensitivity C-reactive protein (hsCRP) and left ventricular (LV) function on admission and on day 5 following AMI. In AMI patients on admission, logGGT was associated with logHcy (r = 0.36), uric acid (r = 0.48) and CK-MB activity (r = -0.41). Uric acid remained an independent determinant of serum GGT activity on admission. Significant increase in GGT activity (77.7%) was observed following AMI. On day 5 serum logGGT was significantly associated with LV relative wall thickness (r = -0.37), LV end-diastolic diameter (r = 0.41) and LV fractional shortening (r = -0.36). In addition, a significant positive correlation was found between serum logGGT and loghsCRP (r = 0.41) and logHcy values (r = 0.395), but only LV end-diastolic diameter remained independently associated with serum GGT activity on day 5 following AMI. GGT is associated with oxidative/inflammatory markers and LV diastolic diameter suggesting its potential role in predicting LV dilatation and dysfunction during the early postmyocardial infarction period.

Gamma-glutamyl transferase level predicts the development of hypertension in Hong Kong Chinese

BackgroundPlasma activities of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyl transferase (GGT) are often increased in cardiometabolic diseases. We investigated if hypertension is associated with increased activities of these plasma markers. MethodsWe included 235 hypertensive and 708 normotensive subjects (mean age 47.3±9.6 and 58.0±10.2years respectively) from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000–2004 who had drank <1/week. In the follow-up study in 2005–2008 (CRISPS-3), 126 out of the 708 subjects had developed hypertension. ResultsRaised plasma ALT (OR=1.22 per SD of log-transformed level, P=0.045) and GGT (OR=1.38 per SD of log-transformed level, P=0.001) levels were associated with hypertension at baseline in CRISPS-2 after adjusting for covariates. Among subjects not on anti-hypertensive medications, plasma ALP, ALT and GGT were related to blood pressure (P<0.01). In subjects normotensive at CRISPS-2, plasma GGT, but not ALP, ALT and AST, was an independent predictor of new-onset hypertension at CRISPS-3 (OR=1.38 per SD of log-transformed level, P=0.020 and OR=2.68 for 3rd tertile vs. 1st tertile, P=0.004) after adjusting for covariates. ConclusionsAmong the 4 plasma markers, increased GGT activity is the strongest predictor for existing and new-onset hypertension in Hong Kong Chinese.

Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals

Northern elephant seals experience prolonged periods of absolute food and water deprivation (fasting) while breeding, molting or weaning. The postweaning fast in elephant seals is characterized by increases in the renin-angiotensin system, expression of the oxidant-producing protein Nox4, and NADPH oxidase activity; however, these increases are not correlated with increased oxidative damage or inflammation. Glutathione (GSH) is a potent reductant and a cofactor for glutathione peroxidases (GPx), glutathione-S transferases (GST) and 1-cys peroxiredoxin (PrxVI) and thus contributes to the removal of hydroperoxides, preventing oxidative damage. The effects of prolonged food deprivation on the GSH system are not well described in mammals. To test our hypothesis that GSH biosynthesis increases with fasting in postweaned elephant seals, we measured circulating and muscle GSH content at the early and late phases of the postweaning fast in elephant seals along with the activity/protein content of glutamate-cysteine ligase [GCL; catalytic (GCLc) and modulatory (GCLm) subunits], γ-glutamyl transpeptidase (GGT), glutathione disulphide reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), GST and PrxVI, as well as plasma changes in γ-glutamyl amino acids, glutamate and glutamine. GSH increased two- to four-fold with fasting along with a 40-50% increase in the content of GCLm and GCLc, a 75% increase in GGT activity, a two- to 2.5-fold increase in GR, G6PDH and GST activities and a 30% increase in PrxVI content. Plasma γ-glutamyl glutamine, γ-glutamyl isoleucine and γ-glutamyl methionine also increased with fasting whereas glutamate and glutamine decreased. Results indicate that GSH biosynthesis increases with fasting and that GSH contributes to counteracting hydroperoxide production, preventing oxidative damage in fasting seals.

Genetic Covariance Between γ-Glutamyl Transpeptidase and Fatty Liver Risk Factors: Role of β2-Adrenergic Receptor Genetic Variation in Twins

Plasma levels of gamma-glutamyl transpeptidase (GGT) are associated with risk factors for nonalcoholic fatty liver disease (NAFLD), such as dyslipidemia, insulin resistance (IR), and hypertension. Limited data exist on whether there is genetic covariance between plasma levels of GGT and NAFLD risk factors. Variants of beta2-adrenergic receptor gene (ADRB2) have been associated with dyslipidemia, IR, and hypertension, but its effect on GGT secretion is not known. We estimated the heritability of GGT using a twin-study design and examined the genetic covariance between GGT levels, IR, hypertension, levels of low-density lipoproteins and triglycerides, and ADRB2 variants. We studied phenotypes of 362 twins; the heritabilities of increased GGT activity and genetic covariance with NAFLD risk factors were estimated by variance-component methodology. ADRB2 genotype associations with plasma GGT activity were examined using generalized estimating equations to account for intra-twinship correlations. GGT activity was heritable at 49% +/- 8% of the twin cohort and had significant covariance with IR; insulin, triglyceride, and uric acid levels; and diastolic blood pressure. In generalized estimating equation models, the most common haplotype of ADRB2 was significantly associated with plasma GGT activity. Five single nucleotide polymorphisms in ADRB2 were associated with levels of GGT; ADRB2 haplotypes displayed pleiotropic effects on GGT and triglyceride levels. In a twin study, GGT shared genetic codetermination with traits of metabolic syndrome. The ADRB2 gene had pleiotropic effects on plasma levels of GGT and triglycerides, indicating linked pathways (eg, adrenergic) between genetic susceptibility to NAFLD and metabolic syndrome.

γ-Glutamyl transpeptidase null mice fail to develop tolerance to coumarin-induced Clara cell toxicity

Coumarin was used as a model Clara cell toxicant to test the hypothesis that tolerance to injury requires increased γ-glutamyl transpeptidase (GGT) activity. Wildtype (GGT+/+) and GGT-deficient (GGT−/−) mice on a C57BL/6/129SvEv hybrid background were dosed orally with corn oil (vehicle) or coumarin (200mg/kg). In vehicle-treated mice, Clara cell secretory protein (CC10) expression was distributed throughout the bronchiolar epithelium. After one dose of coumarin, CC10 expression was dramatically reduced and the bronchiolar epithelium was devoid of Clara cells in GGT+/+ and GGT−/− mice. In wildtype mice, 9 doses of coumarin produced tolerance, characterized as a renewed bronchiolar epithelium with Clara cells expressing CC10 along with a 40% increase in total glutathione (GSH) and a 7-fold increase in GGT activity in the lung. In contrast, tolerance was not observed in GGT−/− mice. To assess whether changes in whole lung levels of GSH and GGT activity reflect Clara cell specific changes an enriched population of cells was isolated from female wildtype B6C3F1 mice made tolerant to coumarin. Compared to Clara cells from control mice, GSH and GGT activity increased 3- and 13-fold, respectively. Collectively, these data suggest Clara cell tolerance to coumarin toxicity requires increased GGT activity favoring enhanced GSH synthesis.

The Importance of Gamma‐Glutamyltransferase Activity in Patients with Coronary Artery Disease

In this study, we sought to investigate the relation of gamma-glutamyltransferase (GGT) levels with the significance of coronary artery disease (CAD), clinical presentation, left ventricular (LV) function, and inflammatory activity. A total of 235 patients (mean age: 60.1 +/- 10.5 years, 166 [70%] males) who had coronary angiography were included in the study. Patients who had CAD constituted the study group (Group 1, n=189) and patients who had insignificant coronary disease or normal coronary activity constituted the control group (Group 2, n=46). GGT levels were higher in Group 1 than Group 2 (38.7 +/- 30.9 U/L versus 27.5 +/- 17.5 U/L, p =0.025). Left ventricular ejection fraction (LVEF) was lower in Group 1 than Group 2 (52.6% +/- 11.7% versus 58.8% +/- 11.3%, p < 0.002). GGT activity (40.2 +/- 32.5 U/L versus 29.1 +/- 18.3 U/L, p < 0.002) and c-reactive protein (CRP) levels (33.9 +/- 43.6 mg/dl versus 17.8 +/- 29.8 mg/dl, p < 0.002) were higher, LVEF (52.6% +/- 12.1% versus 56.5% +/- 11.0%, p =0.021) was lower in patients with acute coronary syndrome compared with stable CAD group. In regression analysis, CRP levels (p < 0.0001, odds ratio [OR]=3.77, 95% confidence interval [CI] 0.10 < OR < 0.32), LVEF (p =0.016, OR=- 2.44, 95% CI - 0.95 < OR < - 0.10) and LV end-diastolic pressure (p =0.015, OR=4.31, 95% CI - 1.19 < OR < - 0.13) were independent predictors of GGT activity. The increased GGT activity is related to LV function, clinical stability, and inflammatory activity rather than the severity of CAD. Measurement of GGT activity may be useful in predicting cardiovascular risk.

Plasma Levels of Cell-Free Apoptotic DNA Ladders and Gamma-Glutamyltranspeptidase (GGT) in Diabetic Children

The plasma levels of apoptotic DNA ladders (i.e., apoptosemia) and gamma-glutamyltranspeptidase (GGT) in diabetic outpatients and rats were investigated. Apoptotic DNA ladders were detected in plasma from 26.8% of type 1 (T1) and 18.5% of type 2 (T2) diabetic children 1-20 years of age, 25.7% of hospitalized children and 35.7% of adult RA outpatients, but in only 3.5% of adult pre-op patients. Plasma from 7.7% of young streptozotocin-induced diabetic but not control rats contained apoptotic DNA ladders. Apoptosemia was detected more often in male T1 (31%) and T2 (30.8%) diabetic outpatients than in female T1 (20.8%) and T2 (15.4%) diabetic outpatients. GGT in apoptosemic plasma was significantly higher than in nonapoptosemic plasma from T1 (P = 0.001) but not T2 diabetic children. The highest amounts of apoptotic DNA were detected most often in diabetic children > or =14 years of age. In vitro study results suggest that cell-free apoptotic DNA ladders appear prior to an increase in GGT activity in serum from human blood incubated at 37 degrees C. The results suggest that 24.7% of plasma samples from diabetic children contained apoptotic DNA ladders, the incidence and amounts of apoptotic DNA ladders were higher in the older diabetic children, and GGT was elevated in apoptosemic T1 diabetic children (P = 0.01). The results indicate that "silent" apoptosemia occurs in T1 and T2 diabetic children and suggest elevated GGT in diabetic children could be due to release from apoptotic cells.

Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Up-regulation of activity of γ-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. Intracellular cysteine has been proposed to form toxic adducts with dopamine which can be metabolized to compounds which inhibit CI activity. We have demonstrated that in addition to CI inhibition, GGT activity is up-regulated in dopaminergic cells as a consequence of glutathione depletion. Inhibition of GGT rather than resulting in increased CI inhibition results in exacerbation of this inhibitory effect. This suggests that increased GGT activity is likely an adaptive response to the loss of glutathione to conserve intracellular glutathione content and results in a compensatory effect on CI activity rather than in its inhibition as has been previously widely hypothesized.

The influence of interleukin-1β on γ-glutamyl transpepidase activity in rat hippocampus

Brain infections as well as peripheral challenges to the immune system lead to an increased production of interleukin-1beta (IL-1beta), a cytokine involved in leukocyte-mediated breakdown of the blood-brain barrier. The effects of IL-1beta have been reported to depend on whether the route of administration is systemic or intracerebral. Using 50-day-old male rats, we compared the effects of IL-1beta on brain gamma-glutamyl transpeptidase (GGT; an enzymatic marker of brain capillary endothelium) at 2, 24 and 96 h after either an intravenous (i.v.) injection of 5 microg IL-1beta or an intracerebroventricular (i.c.v. - lateral ventricle) infusion of 50 ng IL-1beta. When the i.v. route was used, the GGT activity underwent small but significant changes; decreasing in the hippocampus 2 h after the i.v. injection, increasing 24 h later and returning to control levels at 96 h. No significant changes in the hippocampal GGT activity were observed at 2 and 24 h following the i.c.v. infusion. The GGT activity in the hypothalamus remained unchanged regardless of the route of IL-1beta administrations. Similar changes in GGT activity were revealed histochemically. The labeling was found mainly in the capillary bed, the changes being most evident in the hippocampal stratum radiatum and stratum lacunosum-moleculare. A transient increase in GGT activity at 24 h, together with a less sharp delineation of GGT-stained vessels, may reflect IL-1beta induced increased turnover of glutathione and/or oxidative stress, that may in turn, be related to altered permeability of the blood-brain barrier in some neurological and mental disorders, including schizophrenia.

4-Hydroxynonenal increases γ-glutamyl transpeptidase gene expression through mitogen-activated protein kinase pathways

γ-Glutamyl transpeptidase (GGT) plays key roles in the metabolism of glutathione. Previous studies have shown that GGT expression was increased by oxidants, but the mechanism remains unclear. In the present study, the effects of 4-hydroxy-2-nonenal (HNE), an electrophilic end product of lipid peroxidation, on GGT expression were investigated in rat lung epithelial type II (L2) cells. We demonstrated that HNE increased GGT activity and mRNA content in both time- and dose-dependent manners. Actinomycin D, an RNA transcription inhibitor, blocked HNE-stimulated increase in GGT mRNA, suggesting transcriptional regulation of GGT mRNA by HNE. Of the seven GGT mRNA transcripts known to be produced from the single rat GGT gene, we found that types I, II, and V-2 were constitutively expressed in L2 cells, but only types I and V-2 were increased by HNE. PD98059 and SB203580, relatively specific inhibitors of the ERK and the p38MAPK kinase pathway, respectively, significantly attenuated HNE induction of both GGT activity and mRNA content. In contrast, studies with JNK inhibitor I, a cell-permeable peptide, indicated that JNK was not involved in the GGT induction by HNE. We also found that GGT induction by HNE could be completely blocked by a cocktail of PD98059 and SB203580, suggesting a combined effect of ERK and p38MAPK pathways in HNE-mediated GGT induction. In conclusion, our results demonstrate that HNE increased GGT expression in rat alveolar type II cells and that the induction of GGT by HNE was mediated through activation of the ERK and p38MAPK pathways.