N-butyldeoxygalactonojirimycin: A more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo

N-Butyldeoxynojirimycin (NB-DNJ) inhibits the cetamide glucosyltransferase which catalyses the first step in glycosphingolipid (GSL) biosynthesis. It has the potential to be used for the treatment of the GSL lysosomal storage diseases and is currently in clinical trials for the treatment of type 1 G aucher's disease. However, NB-DNJ is also a potent inhibitor of other enzym es, including alpha-glucosidase I and II, which could potentially cause sid e effects in patients receiving life-long therapy. We therefore evaluated a potentially more selective GSL biosynthesis inhibitor, N-butyldeoxygalacto nojirimycin (NB-DGJ), in vitro and in vivo. The distribution and degree of GSL depletion in the liver of mice treated with NB-DGJ or NB-DNJ were equiv alent. Mice treated with NB-DGJ had normal body weights and lymphoid organ sizes, whereas NB-DNJ treated mice showed weight loss and partial lymphoid organ shrinkage. NB-DNJ inhibited glycogen catabolism in the liver, whereas NB-DGJ did not. NB-DNJ was also a potent inhibitor of sucrase and maltase in vitro but not of lactase, while NB-DGJ inhibited lactase but not sucrase or maltase, NB-DGJ is therefore more selective than NB-DNJ, and deserves t o be evaluated for human therapy. BIOCHEM PHARMACOL 59;7:821-829, 2000. (C) 2000 Elsevier Science Inc.