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INTRODUCTION

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Leukotrienes (LTs) are inflammatory lipid mediators synthesized from arachidonic acid (C20:4), a 20-carbon polyunsaturated fatty acid that is present in membrane phospholipids. LTs consist of several biochemically distinct forms (LTA4, LTB4, LTC4, LTD4, LTE4) that act through interactions with specific cellular receptors. LTC4, LTD4, and LTE4 are distinct from the other LT species because they are formed by the incorporation of cysteine into their structures and are referred to as cysteinyl-LTs. These lipid mediators are biologically active in allergic and immune reactions, bronchoconstriction, neutrophil and macrophage chemotaxis, and T-cell differentiation. Emerging data also implicate their involvement in neurologic processes.

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PATHOGENESIS AND EPIDEMIOLOGY

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Several rare disorders of LT metabolism have been identified. They can be classified into those that either block LT synthesis or prevent its degradation (Fig. 148-1). All are rare and have an unknown incidence.

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Figure 148-1

Metabolic pathway for leukotriene synthesis and degradation. Enzymes catalyzing reactions are indicated as circled numbers: 1 = 5-lipoxygenase; 2 = LTA4 hydrolase; 3 = LTC4 synthase; 4 = glutathione synthetase; 5 = γ-glutamyl transpeptidase; 6 = dipeptidase; 7 = fatty aldehyde dehydrogenase; and 8 = CYP4F3A. Disorders are enclosed in rectangles. aa, amino acid; GSH, glutathione; 5-HpETE, 5-hydroperoxy-eicosatetraenoic acid.

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Disorders of Leukotriene Synthesis

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The biosynthesis of LT begins with 5-lipooxygenase acting on arachidonic acid to produce the short-lived LTA4, which is the metabolic precursor for the other LTs. LTA4 is enzymatically converted to LTB4, a potent proinflammatory mediator, and is also acted on by LTC4 synthase, which uses glutathione as a co-substrate, to generate LTC4 and the subsequent series of cysteinyl-LTs (LTD4 and LTE4). Deficient LTC4 synthase activity has been described in 2 children who had severely reduced levels of LTC4, LTD4, and LTE4. Since glutathione is a co-substrate for this enzyme, patients with genetic defects in the production of glutathione (eg, glutathione synthetase deficiency) also exhibit reductions of all cysteinyl-LT species. LTC4 is converted to LTD4 by γ-glutamyl transpeptidase, and patients with deficiency of this enzyme accumulate LTC4 and have profound reductions in LTD4 and LTE4. The subsequent metabolic step uses dipeptidase to convert LTD4 to LTE4. One 15-year-old patient with suspected dipeptidase deficiency accumulated LTD4 and had undetectable LTE4.

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Disorders of Leukotriene Degradation

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The degradation of LTB4 (and LTE4) proceeds by ω-oxidation, which adds a hydroxyl group to the C20-carbon of LTB4. This reaction is catalyzed by the P450 enzyme CYP4F3A. 20-Hydroxy-LTB4 is subsequently oxidized via an aldehyde intermediate to 20-carboxy-LTB4...

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