Abstract:
Glutathione (GSH) is an essential antioxidant for cellular defense against oxidative stress. The homeostasis of this tripeptide is critical for maintaining normal cellular function. GSH imbalance could result in many diseases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF), which are known to have extremely low levels of GSH in the airway system. The synthesis of GSH requires glutamate cysteine ligase (GCL), the rate-limiting enzyme in its formation. GCL is comprised of a catalytic subunit (GCLC) and a modifier subunit (GCLM). GCLC carries out all of the catalytic activity but is facilitated by GCLM. Another family of important antioxidant enzymes, glutathione-S-transferases (GSTs), functions through conjugation with GSH. It is well known that GCLC, GCLM and GSTs are polymorphic. The studies presented here characterize the polymorphisms in GCLC, GCLM and GSTs in subjects with IPF or CF and provide evidence that certain polymorphisms can be risk factors for these diseases. Further studies on the trinucleotide repeat (TNR) polymorphism of GCLC suggest that this polymorphism mediates the cell's ability to replete GSH after depletion, through its effects on GCLC mRNA secondary structure, mRNA stability and the initial rate of protein synthesis. These polymorphisms in GCLC, GCLM and GSTs could partly explain variations in disease severity in IPF and CF.