The myeloperoxidase-dependent metabolism of leukotrienes C4, D4, and E4 to 6-trans-leukotriene B4 diastereoisomers and the subclass-specific S-diastereoisomeric sulfoxides.

The mechanism of the metabolic inactivation of leukotrienes C4, D4, and E4 by human polymorphonuclear leukocytes activated by phorbol myristate acetate has been analyzed with the use of activated cells, their supernatants, the isolated components of the myeloperoxidase system, and chemically synthesized hypochlorous acid (HOC1). The metabolic products were resolved by reverse-phase high performance liquid chromatography in one or more solvent systems, and each product was characterized relative to chemically synthesized standards by its reverse-phase high performance liquid chromatography retention time, UV absorption spectrum, nonvascular smooth muscle spasmogenic activity, and immunoreactivity. The phorbol myristate acetate-activated human polymorphonuclear leukocytes converted each of the sulfidopeptide leukotrienes to products identical with synthetic diastereoisomers of 6-trans-leukotriene B4 by the following criteria: retention times in two solvent systems, lambda max of 269 nm with shoulders at 259 and 279 nm, and mass spectral analysis. Each of the sulfidopeptide leukotrienes was simultaneously converted to subclass-specific S-diastereoisomeric sulfoxides which co-chromatographed with synthetic standards, exhibited a bathochromic shift to a lambda max at 284 nm, were fully immunoreactive, and possessed less than 5% spasmogenic activity of the corresponding sulfidopeptide leukotrienes. When the sulfidopeptide leukotrienes were incubated with supernatants of phorbol myristate acetate-activated cells in the presence of 0.1 mM H2O2, with a mixture of 100 milliunits of myeloperoxidase, 0.1 mM H2O2, and 10 mM Cl-, or with chemically prepared HOCl, the metabolic products formed were the same as those obtained with the activated cells, indicating that extracellular inactivation was due to HOCl produced by the action of released myeloperoxidase.