A marker for hepatocellular damage.
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Alanine Transaminase↗
Biomedical subjects
M F Knapen
Publications and source records attributed to M F Knapen.
The glutathione/glutathione-related enzyme system in reproduction.
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Female↗
Glutathione S-transferase isoenzymes in decidua and placenta of preeclamptic pregnancies.
OBJECTIVE: To investigate a possible involvement of glutathione S-transferases, major detoxificating enzymes, in the pathophysiology of preeclampsia. METHODS: Levels of glutathione S-transferase isoforms and enzyme activity were assessed in placental and decidual tissues in 22 preeclamptic and 21 normotensive women. Measured values were analyzed statistically using the Mann-Whitney U test for comparison between groups, and the signed-rank test for comparison within groups. RESULTS: Glutathione S-transferase pi is the main glutathione S-transferase isoform in normal placental and decidual tissue. Lower median placental and decidual glutathione S-transferase pi levels were found in preeclamptic women compared with controls: 1268 (range: 524-3925) and 2185 (range: 503-6578), P = .05, for placenta; 1543 (range: 681-2967) and 2169 (range: 893-3929), P = .02, for decidua. The total amount of glutathione S-transferases in control and preeclamptic pregnancies was higher in decidua than in placenta. CONCLUSION: Reduced levels of glutathione S-transferase class pi in preeclampsia might indicate a decreased capacity of the glutathione/glutathione S-transferase detoxification system. A higher total amount of glutathione S-transferases in decidual tissue might point to a more pronounced protective role of decidua compared with placenta.
Adult↗
Glutathione and glutathione-related enzymes in reproduction. A review.
Glutathione and glutathione-related enzymes are pivotal for the normal functioning of several important biological processes in humans. Glutathione and glutathione-related enzymes are involved in the metabolism and detoxification of cytotoxic and carcinogenic compounds as well as reactive oxygen species. The role of reactive oxygen species in reproduction was the subject of many investigations, and there is compelling evidence for the involvement of these species in the physiology and pathology of both male and female reproductive systems. The glutathione/glutathione-related enzyme system was extensively studied in gynaecological oncology, but to a lesser extent in other topics related to reproduction. In this paper a review is provided on the glutathione/glutathione-related enzyme system in reproduction. Attention is given to its role as a detoxicating system, and as an early marker for disease.
Female↗
Glutathione S-transferase Alpha 1-1 and aminotransferases in umbilical cord blood.
Recent data suggest that levels of glutathione S-transferase Alpha 1-1 in umbilical cord plasma may be a good indicator of neonatal hepatocellular integrity. In order to fully understand the significance of this new marker we compared the values of glutathione S-transferase Alpha 1-1 (GSTA1-1) with that of the well known liver function markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in arterial and corresponding venous umbilical cord blood of 93 patients. In addition, in 49 of these patients maternal venous blood was also studied. Both arterial and venous umbilical cord GSTA1-1 and AST levels were significantly higher than corresponding maternal venous levels, whereas ALT levels were not. Arterial umbilical cord GSTA1-1 correlated significantly with the corresponding AST and ALT levels (R = 0.46, P < 0.0001 and R = 0.41, P < 0.0001, respectively). Arterial umbilical cord AST correlated significantly with corresponding ALT levels (R = 0.58, P < 0.0001). Arterial umbilical cord plasma GSTA1-1 levels were significantly lower in the cesarean delivery group as compared to the vaginal birth group, whereas no difference was noted for AST or ALT. Arterial umbilical cord AST and GSTA1-1 levels correlated significantly with base deficit (R = 0.29, P = 0.005; R = 0.29, P = 0.005, respectively), whereas ALT did not (R = 0.06, P = 0.54). Arterial umbilical cord AST, ALT, and GSTA1-1 levels correlated significantly with birthweight. In conclusion, GSTA1-1 levels as assessed in neonatal umbilical cord blood, being unrelated to maternal levels, seem to be a more sensitive marker for early neonatal hepatocellular integrity as compared to ALT or AST and even might detect impaired hepatocellular integrity due to the vaginal birth process. Umbilical cord GSTA1-1 may provide a valuable indicator of neonatal condition immediately after birth, the clinical relevance of which needs to be further established.
Adult↗
Glutathione and glutathione-related enzymes in decidua and placenta of controls and women with pre-eclampsia.
Pre-eclampsia is a major complication of pregnancy with high morbidity and mortality rates. The aetiology is still unclear but impaired detoxification or enhanced levels of reactive (oxygen) metabolites may contribute to the development or maintenance of pre-eclampsia. Glutathione and glutathione-related enzymes, as one of the major detoxificating and free-radical scavenging systems, may play a role in controlling the disease. Seventeen normotensive pregnant women and 24 pre-eclamptic women were investigated prospectively with respect to placental and decidual levels of total glutathione (GSH), glutathione S-transferase activity (GST), selenium-dependent glutathione peroxidase (SeGPX) and total glutathione peroxidase activity (TGPX, both selenium- and non-selenium-dependent GPX). Decidual levels of glutathione and related enzymes were compared with placental levels, and the investigated parameters in pre-eclampsia were compared with those in normotensive pregnancy by the Mann-Whitney U -test. Clinical data were correlated with biochemical parameters by Spearman's correlation test. Glutathione levels were significantly higher in decidua as compared with placenta. Glutathione levels were elevated in pre-eclampsia and HELLP (haemolysis, elevated liver enzymes, low platelets) as compared to normotensive pregnancy for decidua and in the placenta of patients with pre-eclampsia only. Glutathione S-transferase activity was not different between the two groups. In the placenta of patients with pre-eclampsia+HELLP, total glutathione peroxidase activity was elevated versus controls. Selenium-dependent glutathione peroxidase activity was higher in decidua versus placenta and in decidua of pre-eclamptic versus control subjects. Enhanced glutathione concentrations and glutathione peroxidase activities were often found in placenta and decidua in pre-eclampsia, probably as a compensatory mechanism to prevent further damage by peroxides, (oxygen) radicals or other toxins in the placenta or in the feto-placental interface.
Adult↗
Glutathione S-transferase alpha levels in epileptic and healthy women preconceptionally and throughout pregnancy.
We studied plasma GSTA1-1 concentrations in preconceptionally recruited epileptic women who received antiepileptic drugs (n = 99) and a control group of healthy women (n = 106). Mean plasma GSTA1-1 concentrations in the control group did not show significant changes preconceptionally and throughout pregnancy. Six weeks postpartum, however, a significant increase in the mean plasma GSTA1-1 concentration (p < 0.001) was found as compared to preconceptional levels and levels during pregnancy. The mean plasma GSTA1-1 concentration in epileptic women was significantly higher in the 4th gestational week compared to those determined in healthy pregnant women (1.68 versus 1.08 microg/l, p < 0.001). Values between the groups in the second and third trimester and postpartum period showed no significant differences.
Anticonvulsants↗
Plasma glutathione S-transferase Pi 1-1 measurements in the study of hemolysis in hypertensive disorders of pregnancy.
OBJECTIVE: To investigate the value of plasma glutathione S-transferase Pi1-1(GSTP1-1) measurements in the assessment of hemolysis in hypertensive disorders of pregnancy. METHODS: Plasma GSTP1-1 and haptoglobin levels and serum lactate dehydrogenase (LDH) activity were measured in 81 healthy nonpregnant female blood donors between 20 and 40 years of age, 41 women during uncomplicated normotensive pregnancy, 35 women with pregnancy-induced hypertension, 67 women with preeclampsia, and 34 women with the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Levels in hypertensive pregnancies were compared to levels in normotensive pregnancy, and levels in normotensive pregnancy were compared to levels in blood donors by the Mann-Whitney U-test. RESULTS: Median GSTP1-1 and LDH levels were significantly increased (p < 0.01) and haptoglobin significantly decreased (p < 0.01) in preeclampsia and the HELLP syndrome as compared to normotensive pregnancy. Both GSTP1-1 and LDH levels were significantly higher in normotensive pregnant women as compared to nonpregnant women (p < 0.0001). The percentage of preeclamptic patients (26.9%) or patients with the HELLP syndrome (73.5%) with elevated GSTP1-1 levels was lower than those with elevated LDH (38.8% and 100%, respectively) or decreased haptoglobin levels (41.8% and 97%, respectively). CONCLUSIONS: We conclude that plasma GSTP1-1 levels may provide useful information on hemolysis in hypertensive disorders of pregnancy in addition to serum LDH activity and plasma haptoglobin levels and that the degree of hemolysis in hypertensive disorders of pregnancy, especially in the HELLP syndrome, is probably less prominent than generally assumed.
Adult↗
Plasma glutathione S-transferase alpha 1-1: a more sensitive marker for hepatocellular damage than serum alanine aminotransferase in hypertensive disorders of pregnancy.
OBJECTIVE: Our purpose was to investigate the value of plasma glutathione S-transferase Alpha 1-1 measurements in the assessment of hepatocellular damage in hypertensive disorders of pregnancy. STUDY DESIGN: Patients were recruited at the Department of Obstetrics and Gynecology of the University Hospital, Nijmegen, The Netherlands. Five groups of patients were studied: normotensive pregnancy (n = 87), pregnancy-induced hypertension (n = 48), preeclampsia (n = 79), the syndrome of hemolysis, elevated liver enzymes, and low platelets (n = 39), and serially studied normotensive pregnancy (n = 21). Blood was collected for assessment of plasma glutathione S-transferase Alpha 1-1 levels and serum alanine aminotransferase activity. Levels in hypertensive pregnancies were compared with levels in normotensive pregnancy by the Mann-Whitney U test. Patients were categorized according as to whether their values are below (normal) or above (elevated) the upper normal reference level. The difference in relative magnitude of elevation between the two factors was determined by the Wilcoxon matched-pairs signed-rank test. RESULTS: Plasma levels in the longitudinally studied normotensive pregnancy group did not differ between gestational ages and were not significantly different from those of the normotensive control group. Median levels of glutathione S-transferase Alpha 1-1 and alanine aminotransferase were significantly increased (p < 0.01, p < 0.0001, respectively) in all subgroups of hypertensive pregnancies compared with normotensive pregnancies. When both levels were elevated, the relative magnitude of the increase of glutathione S-transferase Alpha 1-1 levels was significantly higher than that of alanine aminotransferase activity in preeclampsia (p < 0.01) and the syndrome of hemolysis, elevated liver enzymes, and low platelets (p < 0.0001). Almost half the patients with preeclampsia showed elevated levels of alanine aminotransferase and/or glutathione S-transferase Alpha 1-1. CONCLUSION: Plasma glutathione S-transferase Alpha 1-1 measurements may provide a more sensitive indicator of acute hepatic damage in preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelets compared with the assessment of aminotransferase activity and therefore may allow earlier recognition of these syndromes. The clinical benefits of plasma measurements of glutathione S-transferase Alpha 1-1 for monitoring the hepatic condition in the management of these patients need to be elucidated in further studies.
Adolescent↗
Umbilical cord plasma glutathione S-transferase alpha 1-1 levels as a marker of neonatal hepatocellular integrity.
OBJECTIVE: To investigate possible delivery-related impaired neonatal hepatocellular integrity by assessment of arterial and venous umbilical cord plasma levels of glutathione S-transferase Alpha 1-1. METHODS: Glutathione S-transferase Alpha 1-1 levels were assessed in arterial and venous umbilical cord, and maternal venous plasma samples. The influence of maternal, delivery, and neonatal characteristics on arterial umbilical cord glutathione S-transferase Alpha 1-1 levels was studied, using linear regression analysis after log-transformation. RESULTS: Median (range) arterial umbilical cord glutathione S-transferase Alpha 1-1 plasma levels were higher than venous umbilical cord levels (9.68 [0.64-1125] microg/L and 7.66 [0.78-987.5] microg/L, respectively, P < .005). Median (range) arterial and venous umbilical cord glutathione S-transferase Alpha 1-1 levels were higher than, and did not correlate with, maternal venous plasma levels (8.79 [1.79-183] microg/L and 6.47 [1.58-164.5] microg/L versus 1.47 [0.46-10.4] microg/L, P < .001). Neonates born vaginally demonstrated higher median (range) levels than those delivered by cesarean (13.41 [1.02-1125] microg/L and 5.73 [0.64-172.90] microg/L, respectively, P < .001). Neonates with unfavorable pH (arterial pH under 7.20) demonstrated higher median (range) levels than those with normal pH (arterial pH at least 7.20) (15.15 [0.77-1125] microg/L and 8.82 [0.64-120.90] microg/L, respectively, P < .001). Stepwise multiple linear regression analysis showed that birth weight had the largest influence on arterial umbilical cord glutathione S-transferase Alpha 1-1 levels, followed by arterial base deficit, and route of delivery. CONCLUSION: Arterial umbilical cord glutathione S-transferase Alpha 1-1 plasma levels, being unrelated to maternal venous levels, might give a reliable impression of early neonatal hepatocellular integrity and may become an additional indicator of neonatal condition immediately after birth.
Adolescent↗
Low whole blood glutathione levels in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets syndrome.
OBJECTIVE: To investigate the pathophysiologic involvement of glutathione in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. METHODS: Total whole blood glutathione levels were measured by high performance liquid chromatography in 23 women with pregnancies complicated by preeclampsia or the HELLP syndrome and in 22 normotensive gravidas. Total glutathione levels and the total glutathione/hemoglobin ratios of patients were compared with those of controls by the Mann-Whitney U test. RESULTS: Median total glutathione levels were lower in preeclamptic pregnancies or those complicated by the HELLP syndrome than in normotensive pregnancies (647 [range 268-986] and 750 [range 495-1572] micromol/L, P = .05). The median total glutathione/hemoglobin ratios were significantly lower in preeclamptic pregnancies or in those complicated by the HELLP syndrome than in normotensive pregnancies (0.079 [range 0.033-0.122] and 0.101 [range 0.073-0.210], P = .02). CONCLUSION: Decreased total glutathione levels in maternal whole blood might indicate decreased detoxificating or free radical scavenging capacity in pregnancies complicated by preeclampsia or the HELLP syndrome.
Adult↗
Localization of glutathione S-transferases alpha and pi in human embryonic tissues at 8 weeks gestational age.
Glutathione S-transferases (GST) are a family of enzymes involved in the detoxification of xenobiotics. In humans, GST are divided into four different classes, alpha, mu, pi and theta, with partly overlapping substrate specificity and a tissue-specific expression pattern. We studied the cellular distribution of GST alpha and pi in a variety of human embryonic organs obtained from an extra-uterine monozygotic twin pregnancy at 8 weeks' gestational age. Tissues were fixed in 4% paraformaldehyde and embedded in paraffin. Three 4 microm thick sections were used, one for routine haematein and eosin staining, the others for immunohistochemical determination using monoclonal and polyclonal antibodies against GST alpha and pi, respectively. Both GST alpha and pi were present in hepatocytes, gastrointestinal epithelium, adrenal gland medulla, and tela chorioidea in the telencephalon. GST pi, but not alpha, was found in the epithelium of pancreatic and pulmonary glands, trachea, nephrons and urinary collecting ducts, as well as in the pia mater of the telencephalon and in developing nerve tissue in the gastrointestinal muscularis mucosae. In summary, we have demonstrated that immunoreactive protein for both GST alpha and pi is expressed in the human embryo at 8 weeks' gestational age. The early expression of GST alpha and pi in the epithelia of the urinary and digestive tracts and the respiratory system supports the importance of GST in the detoxification of potentially toxic or carcinogenic compounds. Our results suggest that the embryo itself is capable of detoxifying noxious compounds that are generated intracellularly or that cross the trophoblastic tissue.
Adrenal Glands↗
Chlorpromazine down-regulates tumor necrosis factor-alpha and attenuates experimental multiple organ dysfunction syndrome in mice.
OBJECTIVES: Chlorpromazine is a known modulator of tumor necrosis factor (TNF)-alpha production. TNF-alpha is thought to be a key mediator in the development of the multiple organ dysfunction syndrome (MODS). We investigated the effect of chlorpromazine on the development of zymosan-induced MODS in mice and on plasma TNF-alpha concentrations and production capacity of TNF-alpha by peritoneal cells. DESIGN: Prospective, controlled laboratory study on zymosan-induced generalized inflammation in mice. SETTING: Animal research laboratory. SUBJECTS: C57BL/6 mice received daily doses (4 mg/kg body weight) of chlorpromazine, beginning 2 days before or 5 days after zymosan administration. In additional groups, the daily chlorpromazine dose of 4 mg/kg started 5 days after zymosan was increased 2 days later to 8 or 16 mg/kg/day. MEASUREMENTS AND MAIN RESULTS: The animals were monitored for survival, condition, body weight, and body temperature. Twelve days after zymosan was administered, all surviving animals were killed to obtain plasma, organs, and peritoneal cells. Plasma concentrations of TNF-alpha and lipopolysaccharide-stimulated production of TNF-alpha by peritoneal cells were measured. Organ weights were recorded as an indicator for organ damage. Although survival was not improved when the animals were treated with chlorpromazine, the chlorpromazine-treated survivors showed improved body weight and temperature when compared with the animals receiving zymosan only. Also, the organ weights and lung damage improved significantly in the treated group. Chlorpromazine was most effective when started before zymosan administration. When administered afterward, clinical improvement declined with the dose. In all cases, circulating TNF-alpha and production of TNF-alpha by peritoneal macrophages were lowered toward control values. CONCLUSION: Chlorpromazine mitigates the development of zymosan-induced MODS, possibly by reducing macrophage TNF-alpha production.
Animals↗
Liver function following pregnancy complicated by the HELLP syndrome.
Serum levels of aminotransferases, lactate dehydrogenase, gammaglutamyl transferase, alkaline phosphatase, albumin and conjugated bilirubin, measured in 54 women at a median of 31 months (range 3-101) after pregnancies complicated by the HELLP syndrome, were not elevated. Total bilirubin levels, however, were elevated in 20% of these women; this represents a significant difference from the prevalence in 151 women with a previous normal pregnancy (chi2 = 12.23, P < 0.001), or in the normal female population (chi2 = 22.34, P < 0.00001). This raises the possibility that a dysfunction of the bilirubin-conjugating mechanism represents a risk factor for the development of the HELLP syndrome.
Adult↗
Effects of hormone replacement therapy on plasma glutathione S-transferase A1-1 concentrations in healthy postmenopausal women.
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Dose-Response Relationship, Drug↗
Elimination of various subpopulations of macrophages and the development of multiple-organ dysfunction syndrome in mice.
OBJECTIVE: To evaluate the role of specific macrophage subpopulations in the development of zymosan-induced multiple-organ dysfunction syndrome by selective elimination of liver, splenic, alveolar, and peritoneal macrophages. DESIGN: Randomized animal trial. SETTING: Central animal laboratory at the University Hospital Nijmegen, Nijmegen, the Netherlands. ANIMALS: Male C57Bl/6 mice. INTERVENTIONS: Elimination of macrophages was accomplished by administration of multilamellar liposomes that contained dichloromethylene bisphosphonate (Cl2MBP). Intravenous, intratracheal, and intraperitoneal administrations induced an elimination of liver and splenic, alveolar, and peritoneal and omental macrophages, respectively. Zymosan (1 mg/g) was injected intraperitoneally at day 0. The liposomes that contained Cl2MBP were administered before and after zymosan challenge. At day 12, all surviving mice were killed. MAIN OUTCOME MEASURES: The body weights, temperatures, and mortality rates of the mice were monitored daily. Relative organ weights (ROWs) were calculated from the lungs, liver, spleen, and kidneys after the mice were killed. RESULTS: The liposomes that contained Cl2MBP, administered intravenously before or after zymosan challenge, did not induce significant changes in the body weight, temperature, or mortality rate. The ROW of the liver was significantly decreased in both treatment groups. Elimination of liver and splenic macrophages after zymosan challenge induced an increased ROW of the lung and a decreased ROW of the liver. The liposomes that contained Cl2MBP, administered intratracheally before zymosan challenge, completely prevented deaths. The body weights, temperatures, and ROWs of the mice were not changed. The liposomes that contained Cl2MBP, administered intraperitoneally, did not change the body weight, temperature, or ROW. The liposomes that contained Cl2MBP, administered intraperitoneally before zymosan challenge, increased the mortality from 50% to 90%. CONCLUSIONS: These data show that the elimination of specific macrophage subpopulations and the elimination on specific time points in this model had differential effects, indicating a differential role of specific macrophage subpopulations, either protective or detrimental, in the development of multiple-organ dysfunction syndrome.
Animals↗
Glutathione S-transferases in human ovarian follicular fluid.
OBJECTIVE: To study the levels of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 in human preovulatory ovarian follicular fluid (FF) and pooled granulosa and cumulus cells. DESIGN: The relation of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 with P and 17 beta-E2 concentrations were studied. SETTING: The Department of Obstetrics and Gynecology, the Department of Gastroenterology, and the Laboratory of Endocrinology and Reproduction of the University Hospital Nijmegen in Nijmegen, the Netherlands. PATIENT(S): Infertile women participating in an IVF program. RESULT(S): Detectable amounts of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 were found in ovarian FF and pooled cumulus and granulosa cells. Concentrations of glutathione S-transferase Alpha 1-1 were always much higher than those of glutathione S-transferase Pi 1-1. Both ovarian FF concentrations of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 did not correlate with ovarian FF concentrations of 17 beta-E2 and P. CONCLUSION(S): The high FF concentrations of glutathione S-transferase Pi 1-1 and especially of glutathione S-transferase Alpha 1-1 suggest that these enzymes may play an important role in the detoxification processes in the follicles. The lack of correlation between follicular P and 17 beta-E2 and glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 indicates that both enzymes presumably are not present as a result of the high steroid levels.
Estradiol↗
Organ damage is preceded by changes in protein extravasation in an experimental model of multiple organ dysfunction syndrome.
Our objective was to determine the serial evolution of vascular permeability as measured by protein extravasation in various organs during the development of zymosan-induced multiple organ dysfunction syndrome (MODS). We evaluated the biodistribution of 111Indium-labeled nonspecific polyclonal immunoglobulin G (111In-IgG). On days 2, 5, 8, and 12 after intraperitoneal challenge with 1 mg/g zymosan, mice were killed. Heart, liver, spleen, kidneys, and the mesenteric lymph node complex and tissue samples of muscle, ileum, and colon were dissected free and weighed. 24 h before death, 10 micrograms of IgG labeled with 2 MBq 111In was injected i.v. Relative organ weights (ROW), wet to dry weight ratios (WDR), and a permeability index (PI) were calculated. ROW increased gradually until day 12. WDR also increased gradually in most organs. Lung WDR, however, initially increased, with a subsequent return to normal. Splenic WDR did not change over time. Liver, spleen, ileum, and colon PI were the highest on day 2, followed by a decrease toward normal. Lung PI showed a triphasic course with peak values at days 2 and 12. Mesenteric lymph node complex-PI was continuously elevated. WDR (tissue edema) and PI (protein extravasation) have different courses in various organs. Most organs displayed an early increase in PI, followed by a late decrease, while ROW (organ damage) was still increasing. It appears that organ damage is preceded by an increased protein extravasation.
Animals↗