γ-Glutamyl Leukotrienase Cleavage of Leukotriene C₄

Abstract

The cysteinyl leukotrienes are powerful mediators of vaso- and bronchoconstriction, edema formation, and mucus secretion¹. They appear to play a key role in asthma and may be involved in cardiac and renal disease as well^1–8. The parent compound, leukotriene C₄ (LTC₄), is formed by the conjugation of leukotriene A₄ with glutathione (GSH). Thus it may be expected that the metabolism of LTC₄ resembles GSH conjugates formed with carcinogens, toxins, and xenobiotics⁹. Until recently, the only enzyme known to metabolize this class of compounds as well as GSH itself was γ-glutamyl transpeptidase (GGT)^10–12. GSH conjugates including LTC₄ are metabolized to their cysteinylglycine derivatives. In the case of LTC₄ the resulting leukotriene is LTD₄. This compound is the most potent of the cysteinyl leukotrienes and has been found to be a consistently more effective agonist than LTC₄ and 10 to 100 times more effective than LTE₄, a metabolite of LTD₄ ^13–16. LTC₄ is synthesized in the liver and is secreted into the bile¹⁵. It is also produced in peripheral tissues^1,2,16. Conversion of LTC₄ to LTD₄ is not well understood although it is believed to occur extracellularly because GGT is an ectoenzyme^10–17. We became interested in cysteinyl leukotriene metabolism when we developed mice deficient in GGT¹⁸. Our subsequent studies unexpectedly showed that GGT-deficient mice are competent to metabolize LTC₄.