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glutathione-related enzyme system in reproduction
European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 127–129
www.elsevier.com / locate / ejogrb
Guest Editorial
The glutathione / glutathione-related enzyme system in reproduction Maarten F.C.M. Knapen MD, PhD* Department of Obstetrics and Gynecology, University Hospital St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands Accepted 25 October 1999
The glutathione / glutathione-related enzyme system (GSH / GSH-related enzyme system), in a quantitative sense, is one of the most important protective systems in humans. GSH and GSH-related enzymes are involved in the metabolism and detoxification of cytotoxic and carcinogenic compounds as well as reactive oxygen species (ROS) [1]. The role of ROS in reproduction has been the subject of many investigations, and there is compelling evidence for the involvement of ROS in the physiology and pathology of both female and male reproductive organs [2]. The GSH / GSH-related enzyme system has extensively been studied in gynecologic oncologic disease, for a review see Beckett and Hayes [1]. Relatively little attention has been given so far to the study of this important detoxicating and scavenging system in the etiology and pathophysiology of reproduction-related non-oncologic disease, such as hypertensive disorders of pregnancy [3]. In a recent PhD-thesis [4] and in a recent article in this journal [5], a comprehensive summary on the GSH / GSHrelated enzyme system and several studies on this topic, related to reproductive disorders is presented. The GSH / GSH-related enzyme system is one of the most important protective enzyme systems in humans. The tripeptide glutathione (GSH; L-g-glutamyl-L-cysteinylglycine) plays a central role in the protection of cells against oxidative and electrophilic stress and radiation [6]. GSH can act either as a substrate in the cytosolic GSHredox cycle, or is able to directly inactivate ROS. Currently a myriad of functions is known, and many of them are vital. Some of these important functions are: (a) the detoxification of xenobiotics [1], (b) removal of hydrogen peroxide and other peroxides as well as oxygen free
*Tel.: 131-24-3614741; fax: 131-24-3619036. E-mail address: [email protected] (M.F.C.M. Knapen)
radicals [5], (c) maintenance of free protein sulfhydryl groups [7] and (d) the synthesis of leukotriene C 4 and derivatives. The metabolism of foreign compounds usually involves two distinct stages, commonly referred to as phases I and II. Phase I metabolism involves an initial oxidation, reduction or dealkylation of the xenobiotic by cytochrome P450 mono-oxygenases [8]. Phase II metabolism generally adds hydrophilic moieties, thereby making a toxin more water soluble and less biologically active. Frequently involved phase II conjugation reactions are catalyzed by GST [1]. The GSTs catalyze the addition of GSH to a wide variety of exogenous compounds such as carcinogens, toxins and drugs [1]. The cytosolic GSTs are a family of enzymes consisting of four main classes, Alpha, Mu, Pi and Theta, each divided into one of more isoforms [1]. GSTs are widely distributed in nature and all eukaryotes appear to possess multiple isoenzymes. The distribution of GST isoenzymes is tissue specific. GST class Alpha is mainly expressed in liver. Two class Alpha subunits have been identified and two homodimeric (GSTA1-1 and GSTA2-2) and a heterodimeric enzyme (GSTA1-2) have been purified from human liver. Plasma or serum GST Alpha is a superior marker for hepatocellular impairment [1]. In contrast with the aminotransferases [aspartate aminotransferase (AST) or alanine aminotransferase (ALT)], which are predominantly located in the periportal hepatocytes, GST Alpha is distributed uniformly across the liver lobule and is present in high amounts. The enzyme in rapidly released into the bloodstream during hepatocellular damage [1]. Furthermore, when the active phase of hepatocellular impairment is over, plasma concentrations of GST Alpha more rapidly revert to normal, a feature of the short half-life (under 90 min [9]). For GST class Pi, so far one isoform is descibed: GSTP1-1, which is expressed as the major form in many organs such as erythrocytes, lung, breast, placenta, large intestine and urinary bladder [1]. Plasma levels of GSTP1-
0301-2115 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00261-4
128
M.F.C.M. Knapen / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 127 – 129
1 have been advocated as a marker for hemolysis, because of its abundant presence in erythrocytes [10]. Glutathione peroxidases (GPX) are enzymes that catalyze the reduction of organic hydroperoxides or hydrogen peroxide by GSH. Two major types of GPX have been found. One type is distinguished by containing selenium in the form of a covalently bound selenocysteine in its active site (SeGPX) and is active with both organic hydroperoxides and hydrogen peroxide. The other type of GPX consists of proteins that do not depend on selenium for catalysis and have negligible activity with hydrogen peroxide [11]. The aforementioned thesis [4] mainly comprises studies on the pathophysiological involvement of the GSH / GSHrelated enzyme system in hypertensive disorders of pregnancy and studies on markers for neonatal hepatocellular integrity. GSH levels in decidual tissue of both preeclamptic and normotensive pregnant women showed to be higher than in any human tissue studied before [12]. In preeclampsia, placental and decidual GSH levels were higher than those in normotensive pregnancy, while SeGPX activity was higher in decidual tissue, and selenium-independent GPX was higher in placental tissue, as compared to normotensive pregnancy. Venous GSH levels, corrected for hemoglobin values, were significantly lower in those patients as compared to normotensive pregnancy [13]. These results may indicate that an enhanced GSH / GSH-related enzyme system in placental and decidual tissue may act as a protective mechanism to prevent local tissue damage or spill of oxygen free radicals from the feto-maternal interface to the peripheral circulation. This might be at the expense of materal whole blood glutathione. A decrease of maternal whole blood glutathione levels may result from several mechanisms: (a) an increased turnover, as a result of the inactivation of oxygen free radicals or circulating toxins by this molecule, (b) a decreased provision of glutathione precursors by the liver and kidney as a result of damage to these organ systems, or (c) donation of GSH to the fetomaternal interface [4]. Next to studies on the pathofysiological involvement of the GSH / GSH-related enzyme system in hypertensive disorders of pregnancy, GSTA1-1 and GSTP1-1 were studied as markers for hepatocellular impairment and hemolysis [4,14–16]. GSTA1-1 proved to be a more sensitive marker for hepatocellular integrity in hypertensive disorders of pregnancy, especially in preeclampsia and the HELLP syndrome (Fig. 1). Furthermore, measurements of both GSTA1-1 and ALT indicated signs of hepatocellular damage in approximately 50% of patients with preeclampsia, which is far more than the reported 30% in literature [14]. The hepatocellular integrity in neonates born to mothers with HELLP syndrome was assessed by umbilical cord plasma GSTA1-1 measurements. In contrast with the markedly elevated maternal levels, neonatal levels were in the normal range [15]. The HELLP syndrome may be
Fig. 1. GSTA1-1 and alanine aminotransferase (ALT) as multiple of the upper normal reference level for pregnancy-induced hypertension (d), preeclampsia (s) and the HELLP syndrome (m).
caused by (placenta-derived) endogenous toxins or oxygen free radicals. The latter study may indicate that these substances either do not cross the placenta or indicate that the fetus is not susceptible to their effects [15]. The assessment of hemolysis in hypertensive disorders of pregnancy is a diagnostic difficulty. Serum lactate dehydrogenase activity (LDH) or haptoglobin levels may not specifically indicate hemolysis in these multisystem disorders, because they are characterized by hepatocellular damage as well. Hepatocellular damage is characterized by elevated LDH levels as well, since LDH-5 subtypes, leaking from hepatocellular tissue, contribute to total LDH levels. Haptoglobin is synthesized by the liver and hepatocellular damage may result in low haptoglobin levels as well. Besides this, peripheral blood smears for fragmented erythrocytes may not detect these cells when they are trapped in thrombi and affected arterioles. Plasma GSTP11 is abundantly present in erythrocytes, absent in hepatocellular tissue and is a good marker for hemolysis in hematologic disease [10]. The evaluation of LDH, haptoglobin and GSTP1-1 levels in hypertensive disorders of pregnancy suggests that the estimation of hemolysis by measurements of GSTP1-1 in plasma points to a lower degree of hemolysis than the commonly used markers [16]. An additional study in the discussed thesis demonstrated that several markers for liver function, including GSTA1-1 normalized 6 to 8 weeks after pregnancies complicated by the HELLP syndrome. Interestingly, this study indicated that one out of twenty former HELLP patients had signs of Gilbert’s syndrome, characterized by a dysfunction of the hepatic UDP-glucuronyltransferase system, which is one of the most important detoxicating systems in humans [17,18].
M.F.C.M. Knapen / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 127 – 129
In the second part of the discussed thesis [4], markers for hepatocellular integrity (AST, ALT and GSTA1-1) were assessed in umbilical cord blood at delivery. The neonatal condition immediately after birth is usually assessed by umbilical cord blood gas analysis and Apgar score estimation. These tests do not necessarily reflect impaired integrity of vital organ systems. Early assessment of hepatocellular integrity may contribute to a correct evaluation of the neonatal condition immediately after birth. AST is not a specific marker for hepatocellular integrity, since other organ systems contain large amounts of AST as well, i.e. hemolysis results in elevated AST levels. ALT activity is a rather insensitive maker, since blood levels only rise relatively long time after the hepatocellular damage has occured. GSTA1-1 is a sensitive and specific marker for hepatocellular integrity, not in the least part due to its centrilobular distribution, as discussed in the first lines of the editorial. AST turned out to be of less value, since umbilical cord AST levels correlated with maternal AST levels. ALT did not seem to rise immediately after birth in hypoxic conditions. GSTA11 seemed to be reliable marker for birth-related neonatal hepatocellular integrity. There were signs of liver damage in neonates with unfavourable umbilical pH (,7.20) immediately after birth. The route of birth seemed to have a significant influence on GSTA1-1 levels: vaginal birth resulted in GSTA1-1 levels twice as high as those in cesarean delivery, suggesting a mild hypoxic stress which may affect centrilobular hepatic cells [19,20]. Currently, our research group is further investigating the role of the GSH / GSH-related enzyme system in hypertensive disorders of pregnancy, focusing its attention on: (a) further characterization of GST isotypes and other important detoxicating systems in these disorders and (b) the identification of genetic polymorphisms of glutathione Stransferase Theta, Mu and Pi in relation to the risk for the development of hypertensive disorders of pregnancy [21].
References [1] Beckett GJ, Hayes JD. Glutathione S-transferases: biomedical applications. Adv Clin Chem 1993;30:281–380. [2] Riley JC, Behrman HR. Oxygen radicals and reactive oxygen species in reproduction. Proc Soc Exp Biol Med 1991;198:781–91. [3] Stark M, Neale L, Woodhead S, Jasani B, Johansen KA, Shaw RW. Hypothesis on functional inadequacy of thioredoxin and related systems in preeclampsia. Hypertens Pregnancy 1997;16:35–46. [4] Knapen MFCM. The glutathione / glutathione-related enzyme system in reproduction. Thesis 1998, Catholic University of Nijmegen, The Netherlands. [5] Knapen MFCM, Zusterzeel PLM, Peters WHM, Steegers EAP. Glutathione and glutathione-related enzymes in reproduction: A review. Eur J Obstet Gynecol Reprod Biol 1999;82:171–84.
129
[6] Shan H, Aw TY, Jones DP. Glutathion dependent protection against oxidative injury. Pharmacol Ther 1990;47:67–71. [7] Inoue M. Glutatione: dynamic aspects of protein mixed disulfide formation. In: Dolphin D, Avramovic O, Poulsen R, editors, Glutathione, chemical, biological and medical aspects. Part B, New York: J Wiley & Sons, 1989, pp. 613–41. [8] Guengerich FP. Oxidation of toxic and carcinogenic chemicals by cytochrome P-450 enzymes. Chem Res Toxicol 1991;4:391–407. [9] Tiainen P, Hockerstedt K, Rosenberg PH. Hepatocellular integrity in liver donors and recipients indicated by glutathione transferase alpha. Transplantation 1996;61:904–8. [10] Yoshizaki Y, Yaga K, Fujii Y, Kaneko T. Radioimmunoassay for erythrocyte acidic GSH transferase. Acta Haematol 1989;81:56–7. [11] Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science 1973;179:588–90. [12] Knapen MFCM, Peters WHM, Mulder TPJ, Merkus HMWM, Jansen JBMJ, Steegers EAP. Glutathione and glutathione-related enzymes in decidua and placenta of controls and women with pre-eclampsia. Placenta 1999;20:541–6. [13] Knapen MFCM, Mulder TPJ, Van Rooij IALM, Peters WHM, Steegers EAP. Low whole blood glutathione levels in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets syndrome. Obstet Gynecol 1998;92:1012–5. [14] Knapen MFCM, Mulder TPJ, Bisseling JGA, Penders RHMJ, Peters WHM, Steegers EAP. Plasma glutathione S-transferase Alpha 1-1: a more sensitive marker for hepatocellular damage than alanine aminotransferase in hypertensive disorders of pregnancy. Am J Obstet Gynecol 1998;178:161–5. [15] Knapen M, Van Schaijk F, Mulder T, Peters W, Steegers E. Marker for liver damage in neonates born to mother with HELLP syndrome. Lancet 1997;439:519–20. [16] Knapen MFCM, Peters WHM, Mulder TPJ, Merkus JMWM, Jansen JBMJ, Steegers EAP. Plasma glutathione S-transferase Pi 1-1 measurements in the study of hemolysis in hypertensive disorders of pregnancy. Hypertens Pregnancy 1999;18:147–56. [17] Knapen MFCM, Van Altena AM, Peters WHM, Merkus HMWM, Jansen JBMJ, Steegers EAP. Liver function following pregnancy complicated by the HELLP syndrome. Br J Obstet Gynaecol 1998;105:1208–10. [18] Knapen MFCM, Peters WHM, Steegers EAP. Liver function tests in pregnancies complicated by hypertensive disorders of pregnancy or the HELLP syndrome. Contemp Rev Obstet Gynecol 1999;11:105– 12. [19] Knapen MFCM, Van der Wildt B, Sijtsma EG, Peters WHM, Roelofs HMJ, Steegers EAP. Glutathione S-transferase Alpha 1-1 and aminotransferases in umbilical cord blood. Early Hum Dev 1999;54:129–35. [20] Knapen MFCM, Wong WY, Mulder TPJ, Peters WHM, Merkus HMWM, Steegers EAP. Umbilical cord plasma glutathione Alpha 1-1 levels as a marker of neonatal hepatocellular integrity. Obstet Gynecol 1998;91:490–4. [21] Zusterzeel PLM, Visser W, Peters WHM, Hermsen KJM, Merkus JMWM, Wallenburg HCS, Nelen WLDM, Steegers EAP. Polymorphisms of glutathione S-transferase Theta and Pi and the risk for preeclampsia and the hemolysis, elevated liver enzymes, low platelets syndrome (abstract). Joint meeting of the Dutch and the ¨ Belgian Society of Hypertension, Molndorf Luxemburg, September 1998.
www.elsevier.com / locate / ejogrb
Guest Editorial
The glutathione / glutathione-related enzyme system in reproduction Maarten F.C.M. Knapen MD, PhD* Department of Obstetrics and Gynecology, University Hospital St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands Accepted 25 October 1999
The glutathione / glutathione-related enzyme system (GSH / GSH-related enzyme system), in a quantitative sense, is one of the most important protective systems in humans. GSH and GSH-related enzymes are involved in the metabolism and detoxification of cytotoxic and carcinogenic compounds as well as reactive oxygen species (ROS) [1]. The role of ROS in reproduction has been the subject of many investigations, and there is compelling evidence for the involvement of ROS in the physiology and pathology of both female and male reproductive organs [2]. The GSH / GSH-related enzyme system has extensively been studied in gynecologic oncologic disease, for a review see Beckett and Hayes [1]. Relatively little attention has been given so far to the study of this important detoxicating and scavenging system in the etiology and pathophysiology of reproduction-related non-oncologic disease, such as hypertensive disorders of pregnancy [3]. In a recent PhD-thesis [4] and in a recent article in this journal [5], a comprehensive summary on the GSH / GSHrelated enzyme system and several studies on this topic, related to reproductive disorders is presented. The GSH / GSH-related enzyme system is one of the most important protective enzyme systems in humans. The tripeptide glutathione (GSH; L-g-glutamyl-L-cysteinylglycine) plays a central role in the protection of cells against oxidative and electrophilic stress and radiation [6]. GSH can act either as a substrate in the cytosolic GSHredox cycle, or is able to directly inactivate ROS. Currently a myriad of functions is known, and many of them are vital. Some of these important functions are: (a) the detoxification of xenobiotics [1], (b) removal of hydrogen peroxide and other peroxides as well as oxygen free
*Tel.: 131-24-3614741; fax: 131-24-3619036. E-mail address: [email protected] (M.F.C.M. Knapen)
radicals [5], (c) maintenance of free protein sulfhydryl groups [7] and (d) the synthesis of leukotriene C 4 and derivatives. The metabolism of foreign compounds usually involves two distinct stages, commonly referred to as phases I and II. Phase I metabolism involves an initial oxidation, reduction or dealkylation of the xenobiotic by cytochrome P450 mono-oxygenases [8]. Phase II metabolism generally adds hydrophilic moieties, thereby making a toxin more water soluble and less biologically active. Frequently involved phase II conjugation reactions are catalyzed by GST [1]. The GSTs catalyze the addition of GSH to a wide variety of exogenous compounds such as carcinogens, toxins and drugs [1]. The cytosolic GSTs are a family of enzymes consisting of four main classes, Alpha, Mu, Pi and Theta, each divided into one of more isoforms [1]. GSTs are widely distributed in nature and all eukaryotes appear to possess multiple isoenzymes. The distribution of GST isoenzymes is tissue specific. GST class Alpha is mainly expressed in liver. Two class Alpha subunits have been identified and two homodimeric (GSTA1-1 and GSTA2-2) and a heterodimeric enzyme (GSTA1-2) have been purified from human liver. Plasma or serum GST Alpha is a superior marker for hepatocellular impairment [1]. In contrast with the aminotransferases [aspartate aminotransferase (AST) or alanine aminotransferase (ALT)], which are predominantly located in the periportal hepatocytes, GST Alpha is distributed uniformly across the liver lobule and is present in high amounts. The enzyme in rapidly released into the bloodstream during hepatocellular damage [1]. Furthermore, when the active phase of hepatocellular impairment is over, plasma concentrations of GST Alpha more rapidly revert to normal, a feature of the short half-life (under 90 min [9]). For GST class Pi, so far one isoform is descibed: GSTP1-1, which is expressed as the major form in many organs such as erythrocytes, lung, breast, placenta, large intestine and urinary bladder [1]. Plasma levels of GSTP1-
0301-2115 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00261-4
128
M.F.C.M. Knapen / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 127 – 129
1 have been advocated as a marker for hemolysis, because of its abundant presence in erythrocytes [10]. Glutathione peroxidases (GPX) are enzymes that catalyze the reduction of organic hydroperoxides or hydrogen peroxide by GSH. Two major types of GPX have been found. One type is distinguished by containing selenium in the form of a covalently bound selenocysteine in its active site (SeGPX) and is active with both organic hydroperoxides and hydrogen peroxide. The other type of GPX consists of proteins that do not depend on selenium for catalysis and have negligible activity with hydrogen peroxide [11]. The aforementioned thesis [4] mainly comprises studies on the pathophysiological involvement of the GSH / GSHrelated enzyme system in hypertensive disorders of pregnancy and studies on markers for neonatal hepatocellular integrity. GSH levels in decidual tissue of both preeclamptic and normotensive pregnant women showed to be higher than in any human tissue studied before [12]. In preeclampsia, placental and decidual GSH levels were higher than those in normotensive pregnancy, while SeGPX activity was higher in decidual tissue, and selenium-independent GPX was higher in placental tissue, as compared to normotensive pregnancy. Venous GSH levels, corrected for hemoglobin values, were significantly lower in those patients as compared to normotensive pregnancy [13]. These results may indicate that an enhanced GSH / GSH-related enzyme system in placental and decidual tissue may act as a protective mechanism to prevent local tissue damage or spill of oxygen free radicals from the feto-maternal interface to the peripheral circulation. This might be at the expense of materal whole blood glutathione. A decrease of maternal whole blood glutathione levels may result from several mechanisms: (a) an increased turnover, as a result of the inactivation of oxygen free radicals or circulating toxins by this molecule, (b) a decreased provision of glutathione precursors by the liver and kidney as a result of damage to these organ systems, or (c) donation of GSH to the fetomaternal interface [4]. Next to studies on the pathofysiological involvement of the GSH / GSH-related enzyme system in hypertensive disorders of pregnancy, GSTA1-1 and GSTP1-1 were studied as markers for hepatocellular impairment and hemolysis [4,14–16]. GSTA1-1 proved to be a more sensitive marker for hepatocellular integrity in hypertensive disorders of pregnancy, especially in preeclampsia and the HELLP syndrome (Fig. 1). Furthermore, measurements of both GSTA1-1 and ALT indicated signs of hepatocellular damage in approximately 50% of patients with preeclampsia, which is far more than the reported 30% in literature [14]. The hepatocellular integrity in neonates born to mothers with HELLP syndrome was assessed by umbilical cord plasma GSTA1-1 measurements. In contrast with the markedly elevated maternal levels, neonatal levels were in the normal range [15]. The HELLP syndrome may be
Fig. 1. GSTA1-1 and alanine aminotransferase (ALT) as multiple of the upper normal reference level for pregnancy-induced hypertension (d), preeclampsia (s) and the HELLP syndrome (m).
caused by (placenta-derived) endogenous toxins or oxygen free radicals. The latter study may indicate that these substances either do not cross the placenta or indicate that the fetus is not susceptible to their effects [15]. The assessment of hemolysis in hypertensive disorders of pregnancy is a diagnostic difficulty. Serum lactate dehydrogenase activity (LDH) or haptoglobin levels may not specifically indicate hemolysis in these multisystem disorders, because they are characterized by hepatocellular damage as well. Hepatocellular damage is characterized by elevated LDH levels as well, since LDH-5 subtypes, leaking from hepatocellular tissue, contribute to total LDH levels. Haptoglobin is synthesized by the liver and hepatocellular damage may result in low haptoglobin levels as well. Besides this, peripheral blood smears for fragmented erythrocytes may not detect these cells when they are trapped in thrombi and affected arterioles. Plasma GSTP11 is abundantly present in erythrocytes, absent in hepatocellular tissue and is a good marker for hemolysis in hematologic disease [10]. The evaluation of LDH, haptoglobin and GSTP1-1 levels in hypertensive disorders of pregnancy suggests that the estimation of hemolysis by measurements of GSTP1-1 in plasma points to a lower degree of hemolysis than the commonly used markers [16]. An additional study in the discussed thesis demonstrated that several markers for liver function, including GSTA1-1 normalized 6 to 8 weeks after pregnancies complicated by the HELLP syndrome. Interestingly, this study indicated that one out of twenty former HELLP patients had signs of Gilbert’s syndrome, characterized by a dysfunction of the hepatic UDP-glucuronyltransferase system, which is one of the most important detoxicating systems in humans [17,18].
M.F.C.M. Knapen / European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 127 – 129
In the second part of the discussed thesis [4], markers for hepatocellular integrity (AST, ALT and GSTA1-1) were assessed in umbilical cord blood at delivery. The neonatal condition immediately after birth is usually assessed by umbilical cord blood gas analysis and Apgar score estimation. These tests do not necessarily reflect impaired integrity of vital organ systems. Early assessment of hepatocellular integrity may contribute to a correct evaluation of the neonatal condition immediately after birth. AST is not a specific marker for hepatocellular integrity, since other organ systems contain large amounts of AST as well, i.e. hemolysis results in elevated AST levels. ALT activity is a rather insensitive maker, since blood levels only rise relatively long time after the hepatocellular damage has occured. GSTA1-1 is a sensitive and specific marker for hepatocellular integrity, not in the least part due to its centrilobular distribution, as discussed in the first lines of the editorial. AST turned out to be of less value, since umbilical cord AST levels correlated with maternal AST levels. ALT did not seem to rise immediately after birth in hypoxic conditions. GSTA11 seemed to be reliable marker for birth-related neonatal hepatocellular integrity. There were signs of liver damage in neonates with unfavourable umbilical pH (,7.20) immediately after birth. The route of birth seemed to have a significant influence on GSTA1-1 levels: vaginal birth resulted in GSTA1-1 levels twice as high as those in cesarean delivery, suggesting a mild hypoxic stress which may affect centrilobular hepatic cells [19,20]. Currently, our research group is further investigating the role of the GSH / GSH-related enzyme system in hypertensive disorders of pregnancy, focusing its attention on: (a) further characterization of GST isotypes and other important detoxicating systems in these disorders and (b) the identification of genetic polymorphisms of glutathione Stransferase Theta, Mu and Pi in relation to the risk for the development of hypertensive disorders of pregnancy [21].
References [1] Beckett GJ, Hayes JD. Glutathione S-transferases: biomedical applications. Adv Clin Chem 1993;30:281–380. [2] Riley JC, Behrman HR. Oxygen radicals and reactive oxygen species in reproduction. Proc Soc Exp Biol Med 1991;198:781–91. [3] Stark M, Neale L, Woodhead S, Jasani B, Johansen KA, Shaw RW. Hypothesis on functional inadequacy of thioredoxin and related systems in preeclampsia. Hypertens Pregnancy 1997;16:35–46. [4] Knapen MFCM. The glutathione / glutathione-related enzyme system in reproduction. Thesis 1998, Catholic University of Nijmegen, The Netherlands. [5] Knapen MFCM, Zusterzeel PLM, Peters WHM, Steegers EAP. Glutathione and glutathione-related enzymes in reproduction: A review. Eur J Obstet Gynecol Reprod Biol 1999;82:171–84.
129
[6] Shan H, Aw TY, Jones DP. Glutathion dependent protection against oxidative injury. Pharmacol Ther 1990;47:67–71. [7] Inoue M. Glutatione: dynamic aspects of protein mixed disulfide formation. In: Dolphin D, Avramovic O, Poulsen R, editors, Glutathione, chemical, biological and medical aspects. Part B, New York: J Wiley & Sons, 1989, pp. 613–41. [8] Guengerich FP. Oxidation of toxic and carcinogenic chemicals by cytochrome P-450 enzymes. Chem Res Toxicol 1991;4:391–407. [9] Tiainen P, Hockerstedt K, Rosenberg PH. Hepatocellular integrity in liver donors and recipients indicated by glutathione transferase alpha. Transplantation 1996;61:904–8. [10] Yoshizaki Y, Yaga K, Fujii Y, Kaneko T. Radioimmunoassay for erythrocyte acidic GSH transferase. Acta Haematol 1989;81:56–7. [11] Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science 1973;179:588–90. [12] Knapen MFCM, Peters WHM, Mulder TPJ, Merkus HMWM, Jansen JBMJ, Steegers EAP. Glutathione and glutathione-related enzymes in decidua and placenta of controls and women with pre-eclampsia. Placenta 1999;20:541–6. [13] Knapen MFCM, Mulder TPJ, Van Rooij IALM, Peters WHM, Steegers EAP. Low whole blood glutathione levels in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets syndrome. Obstet Gynecol 1998;92:1012–5. [14] Knapen MFCM, Mulder TPJ, Bisseling JGA, Penders RHMJ, Peters WHM, Steegers EAP. Plasma glutathione S-transferase Alpha 1-1: a more sensitive marker for hepatocellular damage than alanine aminotransferase in hypertensive disorders of pregnancy. Am J Obstet Gynecol 1998;178:161–5. [15] Knapen M, Van Schaijk F, Mulder T, Peters W, Steegers E. Marker for liver damage in neonates born to mother with HELLP syndrome. Lancet 1997;439:519–20. [16] Knapen MFCM, Peters WHM, Mulder TPJ, Merkus JMWM, Jansen JBMJ, Steegers EAP. Plasma glutathione S-transferase Pi 1-1 measurements in the study of hemolysis in hypertensive disorders of pregnancy. Hypertens Pregnancy 1999;18:147–56. [17] Knapen MFCM, Van Altena AM, Peters WHM, Merkus HMWM, Jansen JBMJ, Steegers EAP. Liver function following pregnancy complicated by the HELLP syndrome. Br J Obstet Gynaecol 1998;105:1208–10. [18] Knapen MFCM, Peters WHM, Steegers EAP. Liver function tests in pregnancies complicated by hypertensive disorders of pregnancy or the HELLP syndrome. Contemp Rev Obstet Gynecol 1999;11:105– 12. [19] Knapen MFCM, Van der Wildt B, Sijtsma EG, Peters WHM, Roelofs HMJ, Steegers EAP. Glutathione S-transferase Alpha 1-1 and aminotransferases in umbilical cord blood. Early Hum Dev 1999;54:129–35. [20] Knapen MFCM, Wong WY, Mulder TPJ, Peters WHM, Merkus HMWM, Steegers EAP. Umbilical cord plasma glutathione Alpha 1-1 levels as a marker of neonatal hepatocellular integrity. Obstet Gynecol 1998;91:490–4. [21] Zusterzeel PLM, Visser W, Peters WHM, Hermsen KJM, Merkus JMWM, Wallenburg HCS, Nelen WLDM, Steegers EAP. Polymorphisms of glutathione S-transferase Theta and Pi and the risk for preeclampsia and the hemolysis, elevated liver enzymes, low platelets syndrome (abstract). Joint meeting of the Dutch and the ¨ Belgian Society of Hypertension, Molndorf Luxemburg, September 1998.