Role of glutathione in the pathophysiology of pre-eclampsia: implications for nutritional intervention

KEY MESSAGES Pre-eclampsia continues to be a significant contributor to morbidity and mortality in pregnancy. Much evidence has been put forward linking oxidative stress as part of the pathophysiology involved in pre-eclampsia and other hypertensive states of pregnancy. Glutathione, our major endogenous antioxidant, has been found to be relatively depleted in pre-eclampsia patients and it is suggested that the nutritional repletion of glutathione may positively impact outcome in this condition. Introduction Pre-eclampsia is a multisystem disorder of pregnancy and remains one of the leading causes of maternal and perinatal morbidity and mortality globally. Statistics on pre-eclampsia give rise to great concern. Depending on geographic location, it affects between 2% and 5% of pregnancies and leads to the death of over 75,000 women and 500,000 babies worldwide each year.[1] To this degree, doctors and researchers have investigated novel approaches in screening diagnostics.[2] Investigation into safe and inexpensive nutritional interventions for both treatment and prophylaxis is warranted. Raising glutathione is a primary candidate to accomplish these goals. Oxidative stress in pre-eclampsia Oxidative stress (OS) can be simply defined as an imbalance between free radical formation and antioxidant defenses. Free radicals (reactive oxygen species, reactive nitrogen species) potentially lead to a cascade of biochemical events that disrupt normal cellular function. OS has been proposed that they play a part in the pathogenesis of many disease processes including cancer,[3,4] arteriosclerosis,[5–8] Alzheimer’s Disease,[9,10] pulmonary disease,[11,12] and a number of gynecological pathologies including endometriosis,[13–15] gestational diabetes,[16–18] infertility,[19–21] and polycystic ovary syndrome.[22–24] OS has been frequently described in pre-eclampsia and is considered as playing either a causal role or a resulting from the disorder.[25–30] It has been suggested that biomarkers of OS such as lowered glutathione,[31–34] lowered selenium, and increased malondialehyde, be utilized as screening or prognostic measurements.[35–39] Glutathione Glutathione (gamma-glutamylcysteine) often abbreviated as GSH (glutathione sulfhydryl) is a naturally-occurring tripeptide produced by human cells.[40] It is present in all mammalian tissues and is the most abundant non-protein thiol combatting OS.[41] Glutathione/glutathione disulfide (GSH/GSSH) is the major redox couple in animal cells.[42] Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression), DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and xenobiotic detoxification.[43] Human glutathione levels can be augmented through selected oral supplementation of its precursors. Glutathione itself taken orally is not an effective means of raising tissue levels of glutathione in humans.[44–46] The GSH molecule is readily broken down by gamma-glutamyl transferase (GGT) which is uniquely elevated in the human intestine.[47,48] The major limiting factor for the cell’s production of glutathione is the semiessential amino acid cysteine.[49] Supplementation with free L-cysteine or L-cystine is also problematic due to rapid oxidation of these amino acids in the gut and serum.[50] The amino acid methionine can be metabolized into cysteine, but is also a precursor of homocysteine which is considered a risk factor for cardiovascular disease.[51] Cysteine delivery can be enhanced by addition of acetylated side chains (N-acetylcysteine),[52] or other moieties that prevent oxidation such as procysteine (L-2-oxothiazolidine-4-carboxylate),[53] and others. Nutritional supplementation with undenatured whey protein isolate shows great promise, the specially prepared whey protein isolate Immunocal* (*“ABD” in China), has undergone several trials demonstrating its role as a glutathione precursor,[54–58] and appears in the American Physician’s Desktop Reference (PDR).[59] Glutathione in pre-eclampsia and eclampsia Low levels of glutathione (GSH) in pre-eclampsia patients have been described as far back as 1958.[60] Subsequently, investigations have repeatedly demonstrated this correlation and it has been noted that when pregnancy is complicated by pre-eclampsia, there is a precipitous fall in the patient’s antioxidant capacity.[61–70] Moreover, the severity of the condition apparently corresponds directly to the level of glutathione deficiency.[71] It should be noted that low glutathione levels occur in most cases of hypertensive disorders of pregnancy and are not just restricted to pre-eclampsia.[72] Also noted is that the increased risk of pre-eclampsia with maternal age is probably a reflection of the normal drop in GSH status that accompanies aging.[73] Diabetic patients appear to have even lower levels of glutathione when pregnancies are complicated by pre-eclampsia.[74] A similar association among obesity, low GSH levels, and pre-eclampsia has been observed.[75,76] Many researchers have suggested that the measure of GSH could be a marker for risk assessment, providing the opportunity to promptly correct glutathione and antioxidant function.[77–81] Monitoring of these biomarkers can be sensitive early in pregnancy, from 16 weeks of gestation,[82] allowing for early intervention. Of great concern is the finding that low levels of GSH seen in pre-eclampsia may also be found in the children delivered to these mothers.[83–86] Infants with low glutathione status are more prone to a number of associated medical complications including hypoxic encephalopathy, bronchopulmonary dysplasia, retinopathy, sepsis, and more.[87–90] The falling costs and increased accuracy of genetic testing has greatly improved our ability to predict future risks for patients, and to protect them.[91,92] One area of great interest is genetic testing for glutathione enzyme abnormalities. There is much evidence that women with a variety of glutathione enzyme defects are significantly more likely to develop eclampsia and pre-eclampsia.[93–96] Given the benefit of predictive testing, doctors can monitor these issues and address them earlier, hopefully pre-empting their complications.[97,98] GSH deficiency has been linked to the oxidation of circulating fats (lipid peroxidation) in pre-eclamptic patients.[99–103] This damages the sensitive endothelial walls.[104–106] Subsequent constriction of muscles in the artery wall leads to narrowing of the passageways and decreased blood flow. Combined with the demands of gestation, this may trigger a cascade of events leading to full-blown eclampsia.[10,107,108] Chen and his team at the University of Glasgow believe this depletion might account for some of the important symptoms of pregnancy-induced hypertension—excess calcium in cells, reduced elasticity of red blood cells, and damaged blood vessels.[109] Branch’s team at the University of Utah believe that the lipid peroxidation that follows may be part of the disease process that begins when foam cells form in the decidua of pre-eclamptic placentas.[110] The HELLP syndrome is a serious complication of pre-eclampsia. Patients suffer liver damage, breakdown of red blood cells, and loss of platelets. GSH loss is particularly pronounced. Researchers have established a threefold correlation—severity of the pre-eclampsia, cell fragility and the level of GSH oxidation.[111–114] Glutathione augmentation in pre-eclampsia Interventions using various antioxidants in pre-eclampsia have shown mixed results varying in size and study design.[115–118] The GSH precursor N-acetylcysteine has also shown some promise but no definitive large studies have yet confirmed its usefulness.[119–121] Selenium is an integral component of glutathione peroxidase.[122,123] Selenium supplementation can enhance glutathione activity.[124,125] Interventional studies providing selenium supplementation to patients with pre-eclampsia have been promising.[126,127] Several other glutathione-enhancing strategies have been attempted in human trials. A Cambridge University team London attempted to control symptoms in a group of pre-eclamptic patients. Women with severe cases that had stopped responding to traditional therapy were given nitroso-glutathione. Arterial pressure, platelet activation, and uterine artery resistance all improved, with no adverse effects on the fetus.[128] They followed up with a subsequent study that showed an improvement in protein-to-creatinine ratio and a mild lowering of hypertension.[129,130] Conclusions Several decades of research have established that OS is part of the pathophysiology of pre-eclampsia and other hypertensive disorders of pregnancy. Subsequently, studies using antioxidant supplementation have followed. These suggest that early intervention, even pre-conceptual intervention may have some benefit. As the science revolving around glutathione evolves, an increasing number of pathophysiological entities have been identified in which therapeutic interventions have shown to be beneficial. In the case of pre-eclampsia, findings to date call for more clinical research to solidify the evidence on glutathione augmentation as a potential nutritional intervention. If successful, it may offer a cost effective and safe strategy to prevent or treat pre-eclampsia. Funding No funding was received for the writing and preparation of this paper. Author contributions JG provided the concept for this paper and wrote the original framework of the paper. JG also contributed the perspectives on glutathione and antioxidation in hypertensive diseases of pregnancy. AP edited the initial drafts and contributed to the sections on morbidity, mortality, and pathophysiology of pre-eclampsia. Conflicts of interest Dr. Jimmy Gutman is the author of several books on the topic of glutathione. He is also a medical consultant to Immunotec, a nutraceutical company in Canada.

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