Metabolism of leukotriene C₄ in γ-glutamyl transpeptidase-deficient mice

We have investigated the metabolism of leukotriene C₄ (LTC₄) in γ- glutamyl transpeptidase (GGT)-deficient mice (Lieberman, M. W., Wiseman, A. L., Shi, Z-Z., Carter, B. Z., Barrios, R., Ou, C.-N., Chevez-Barrios, P., Wang, Y., Habib, G. M., Goodman, J. C., Huang, S. L., Lebovitz, R. M., and Matzuk, M. M. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 7923-7926) and have found substantial conversion of LTC₄ to leukotriene D₄ by high performance liquid chromatography and continuous flow fast atom bombardment-tandem mass spectrometric analyses. LTC₄-converting activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas and lower activity in liver and lung. The activity is membrane-bound and is inhibited by acivicin, a known inhibitor of GGT. The enzyme was partially purified from the small intestine of GGT- deficient mice by papain treatment and gel filtration chromatography. The partially purified fragment released by papain has an apparent molecular mass of 65-70 kDa and the same substrate specificity as the tissue homogenate. In addition to LTC₄, S-decyl-GSH is also cleaved. GSH itself, oxidized GSH, and the synthetic substrates used to analyze GGT activity (γ-glutamyl-p- nitroanilide and γ-glutamyl-4-methoxy-2-naphthylamide) are not substrates for this newly discovered enzyme. These data demonstrate that in addition to GGT at least one other enzyme cleaves LTC₄ in mice. To reflect this enzyme's preferred substrate, we suggest that it be named γ-glutamyl leukotrienase.