Review Glutathione biochemistry in asthma ☆ Niki L. Reynaert ⁎ Department of Respiratory Medicine, Nutrim School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands abstract article info Article history: Received 17 September 2010 Accepted 21 January 2011 Available online 31 January 2011 Keywords: Glutathione Asthma Oxidative stress Redox balance Glutathione peroxidase Glutathione reductase Glutathione-S-transferase Glutaredoxin Background: Oxidative stress in an important hallmark of asthma and much research has therefore focused on the predominant antioxidant in the lungs, namely the tripeptide glutathione. Major conclusions: In lung samples of patients with asthma increased levels of glutathione are typically observed, which appear to relate to the level of pulmonary inflammation and are therefore regarded as an adaptive response to the associated oxidative stress. Also in blood samples increased total GSH levels have been reported, representing the systemic inflammatory component of the disease. In addition, a number of the antioxidant enzymes involved in the maintenance of the GSH/GSSG ratio as well as enzymes that utilize GSH have been found to be altered in the lungs and blood of asthmatics and will be summarized in this review. Very few studies have however linked enzymatic alterations to GSH levels or found that either of these correlated with disease severity. Some animal studies have started to investigate the pathophysiological role of GSH biochemistry in asthma and have yielded surprising results. Important in this respect is the physiological role of the GSH redox equilibrium in determining the outcome of immune responses, which could be deregulated in asthmatics and contribute to the disease. Scope of review: Clinical data as well as animal and cell culture studies regarding these aspects of GSH in the context of asthma will be summarized and discussed in this review. This article is part of a Special Issue entitled: Biochemistry of Asthma. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The tripeptide glutathione (L-γ-glutamyl-L-cysteinyl-glycine) is the key antioxidant that protects the lungs from free radical mediated injury. Because a large portion of pulmonary oxidative stress occurs on the extracellular surface of the lung epithelium, glutathione is highly abundant in the epithelial lining fluid of the respiratory tract with concentration around 400 μM [1], thereby exceeding plasma levels by 100-fold. Intracellular levels range from 1 to 10 mM and under physiological conditions, 95% of glutathione is in the reduced form [2,3]. Glutathione first of all is a non-enzymatic defense molecule by acting as a sacrificial target for reactive oxygen species (ROS), whereby it becomes oxidized to the dimeric form GSSG. The enzymatic machinery involving glutathione is part of the enzymatic antioxidant defense mechanism. In the glutathione peroxidase (GPx)-catalyzed reduction of H 2 O 2 and organic hydroperoxides GSH acts as a co- substrate and is itself oxidized to GSSG. GSH is recycled back from GSSG at the expense of NADPH by glutathione reductase (GR). Alternatively, GSSG can be excreted by cells. Extracellular glutathione is metabolized by the enzyme γ-glutamyl transferase (GGT), providing L-cysteine, which is taken up by the cells by the L-cys amino acid transport system for internal rebuilding of glutathione [4]. Upon oxidative stress, recycling is not sufficient to maintain the redox state and as an adaptive response de novo synthesis of GSH, in which L-cysteine is first coupled to glutamate by glutamate cysteinyl ligase (GCL) and next to glycine by GSH synthase can be initiated (Fig. 1). In addition, GSH can form adducts with xenobiotics and proteins, reactions which are catalyzed by glutathione-S-transferase (GST) enzymes. The adduct formation with xenobiotics aids in their elimination, whereas the binding to protein thiols is a posttransla- tional modification that is termed S-glutathionylation and protects proteins against irreversible oxidations and can modulate their function. The biochemistry of nitric oxide interaction with glutathione, leading to the formation of S-nitrosoglutathione and protein S-nitrosylation, plays an important role in lung physiology and asthma as well and is addressed elsewhere in this issue. Asthma is a chronic inflammatory disorder caused by a heteroge- neous group of factors, including allergens and chemical irritant exposures in susceptible subjects. Moreover, there are different phenotypes with regard to the age of onset as well as inflammatory profile and response to therapy. Regardless, oxidative stress is considered a hallmark of all subtypes of asthma and is believed to play a pathophysiological role in the disease by causing damage to airway epithelial cells, leading to bronchial hyperresponsiveness and airway obstruction. Oxidative stress and altered redox chemistry that arise from irritant exposure and inflammation are not only linked to damage but importantly have now also been shown to modulate immune responses. Therefore, given the pivotal role of glutathione in Biochimica et Biophysica Acta 1810 (2011) 1045–1051 ☆ This article is part of a Special Issue entitled: Biochemistry of Asthma. ⁎ Tel.: +31 43 3882270; fax: +31 43 3875051. E-mail address: n.reynaert@pul.unimaas.nl. 0304-4165/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2011.01.010 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen