Deficient synthesis of cysteinyl leukotrienes in glutathione synthetase deficiency

Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism. As a consequence of the block in the gamma-glutamyl cycle, the enzyme defect leads to a generalized intracellular GSH deficiency. The cysteinyl leukotrienes (LTs), LTC4, LTD4 and LTE4, are potent lipid mediators generated in the 5-lipoxygenase pathway. LTC4 is derived from the unstable epoxide LTA4 by conjugation with GSH, and therefore GSH is required for LTC4 synthesis. In the circulation LTC4 is rapidly metabolized to LTE4 which is excreted in the urine. In the present study, LT metabolites were separated in a patient with biochemically established GSD and intracellular GSH deficiency (0.5 mM in erythrocytes, normal range 2.0-2.5 mM) by reversed-phase high-performance liquid chromatography, and quantified by enzyme immunoassays. Our results revealed that in GSD LTC4 synthesis is significantly decreased in calcium ionophore A23187-activated monocytes as well as in neutrophils (11-14% and 7-10%, respectively, of the levels detected in the parents or healthy controls). Additionally, urinary LTE4 was also found to be abnormally decreased in GSD (0.4 nmol/mol creatinine as compared to 15-46 nmol/mol creatinine in parents and controls). GSD represents the first described disorder with decreased synthesis of cysteinyl LTs and may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo. Moreover the impaired synthesis of cysteinyl LTs might be involved in the pathophysiology of GSD.