Synthesis and metabolism of leukotrienes in γ-glutamyl transpeptidase deficiency

Abstract

Leukotrienes (LTs) are active lipid mediators derived in the 5-lipoxygenase pathway. LTC4, the primary cysteinyl LT, is cleaved by γ-glutamyl transpeptidase (GGT), resulting in LTD4. We studied the synthesis and metabolism of LTs in three patients with GGT deficiency. LTs were analyzed in urine, plasma, and monocytes after HPLC separation by enzyme immunoassays, radioactivity detection, and electrospray tandem mass spectrometry. Analysis of LTs in urine revealed increased concentrations of LTC4 (12.8–17.9 nmol/mol creatinine; controls, <0.005 nmol/mol creatinine), whereas LTE4 was below the detection limit (<0.005 nmol/mol creatinine; controls, 32.2 ± 8.6 nmol/mol creatinine). In plasma of one patient, LTC4 was found to be increased (17.3 ng/ml; controls, 9.6 ± 0.4 ng/ml), whereas LTD4 and LTE4 were below the detection limit (<0.005 ng/ml). LTB4 was found within normal ranges. In contrast to controls, the synthesis of LTD4 and LTE4 in stimulated monocytes was below the detection limit (<0.1 ng/106 cells; controls, 37.1 ± 4.8 cells and 39.4 ± 5.6 ng/106 cells, respectively). The formation of [3H]LTD4 from [3H]LTC4 in monocytes was completely deficient (<0.1%; controls, 85 ± 7%).Our data demonstrate a complete deficiency of LTD4 biosynthesis in patients with a genetic deficiency of GGT. GGT deficiency represents a new inborn error of cysteinyl LT synthesis and provides a unique model in which to study the pathobiological coherence of LT and glutathione metabolism.

Keywords

• cysteinyl leukotriene
• glutathione
• 5-lipoxygenase pathway