Spectrum of toxicities of amino acid methyl esters for myeloid cells is
determined by distinct metabolic pathways
DL Thiele and PE Lipsky
Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas 75235-8887.
L-leucine methyl ester (Leu-OMe), Leu-Leu-OMe, Phe-OMe, and Glu-(OMe)2 are
toxic to mononuclear phagocytes (M phi) and neutrophils. In the present
studies, the mechanism of this toxicity was examined. A concentration of
NH4Cl known to neutralize lysosomal pH and to block conversion of Leu-OMe
to the dipeptide condensation product Leu-Leu-OMe inhibited Leu-OMe- or
Glu-(OMe)2- but not Leu-Leu-OMe-mediated M phi toxicity. Leu-OMe-,
Glu-(OMe)2-, or Leu-Leu-OMe-mediated killing of M phi was prevented by
Gly-Phe-CHN2, a specific inhibitor of the thiol protease, dipeptidyl
peptidase I (DPPI). Neither NH4Cl nor Gly-Phe-CHN2 prevented
Phe-OMe-mediated M phi toxicity. In contrast, inhibition of M phi serine
esterase activity prevented Phe-OMe- but not Leu-OMe- or Glu-
(OMe)2-mediated killing of M phi. The myeloid tumor lines U937, HL60, and
THP-1 were found to be uniformly enriched in DPPI and susceptible to
Leu-Leu-OMe but not Leu-OMe toxicity. Whereas HL60 were resistant to
Phe-OMe, THP-1 cells were killed by this agent. Incubation of peripheral
blood mononuclear cells with Leu-OMe resulted in loss of natural killer
(NK) functions and cytotoxic T lymphocytes (CTL) precursors, a process that
requires the DPPI-dependent generation of membranolytic polymerization
products. Phe-OMe had no toxic effects on NK cells or CTL precursors. These
results indicate that Leu-OMe and Glu- (OMe)2 toxicity for M phi is related
to the production of higher molecular weight hydrophobic polymerization
products via the sequential action of two nonserine esterase lysosomal
enzymes. In contrast, Phe- OMe toxicity for myeloid cells was found to
correlate with serine esterase-mediated intracellular trapping of high
concentrations of the free amino acid Phe. These distinct enzymatic
mechanisms may provide a unique means of targeting agents capable of
selectively deleting cells of myeloid lineage.
Volume 79,
Issue 4,
pp. 964-971,
02/15/1992
Copyright © 1992 by The American Society of Hematology
