Chapter 148: Disorders of Leukotriene Synthesis and Degradation

INTRODUCTION

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.

PATHOGENESIS AND EPIDEMIOLOGY

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.

Disorders of Leukotriene Synthesis

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.

Disorders of Leukotriene Degradation

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 ...