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Journal of Lipid Research, Vol. 45, 900-904, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Synthesis and metabolism of leukotrienes in -glutamyl transpeptidase deficiency

Ertan Mayatepek^1,*, Jürgen G. Okun, Thomas Meissner^*, Birgit Assmann^*, Judith Hammond, Johannes Zschocke^** and Wolf-Dieter Lehmann

^* Department of General Pediatrics, University Children's Hospital, Düsseldorf, Germany
Department of General Pediatrics, University Children's Hospital, Division of Metabolic and Endocrine Diseases, Heidelberg, Germany
NSW Biochemical Genetics Service, Royal Alexandra Hospital for Children, Sydney, Australia
^** Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
Central Spectroscopy Unit, German Cancer Research Institute, Heidelberg, Germany

¹ To whom correspondence should be addressed. e-mail: mayatepek{at}uni-duesseldorf.de

Leukotrienes (LTs) are active lipid mediators derived in the 5-lipoxygenase pathway. LTC₄, the primary cysteinyl LT, is cleaved by -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.

Supplementary key words cysteinyl leukotriene • glutathione • 5-lipoxygenase pathway

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