Submitted on November 5, 2003
Revised on January 30, 2004
Accepted on January 30, 2004
Synthesis and metabolism of leukotrienes in gamma-glutamyl transpeptidase deficiency
Ertan Mayatepek, Juergen G. Okun, Thomas Meissner, Birgit Assmann, Judith Hammond, Johannes Zschocke, and Wolf-Dieter Lehmann
Department of General Pediatrics, University Children´s Hospital, Duesseldorf 40225
Corresponding Author: mayatepek{at}uni-duesseldorf.de
Leukotrienes (LT)s are active lipid mediators derived in the 5-lipoxygenase pathway. LTC4, the primary cysteinyl leukotriene, is cleaved by gamma-glutamyl transpeptidase (GGT) resulting in LTD4. We studied synthesis and metabolism of LTs in three patients with GGT-deficiency. Leukotrienes were analysed in plasma, urine as well as in stimulated monocytes after HPLC separation by enzyme immunoassays, radioactivity detection and electrospray tandem mass spectrometry. Analysis of LTs in urine of all patients 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, synthesis of LTD4 as well as LTE4 in stimulated monocytes was below the detection limit (<0.1 ng/106 cells; controls 37.1±4.8; 39.4±5.6 ng/106 cells, respectively). Formation of [3H]-LTD4 from [3H]-LTC4 in monocytes was completely deficient (<0.1%; controls 85±7 %). There was no evidence for any inhibitory activity of LTD4-synthesis in the plasma of a GGT-deficient patient. 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 an unique model to study the pathobiological coherences of LT and glutathione metabolism.
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