Jr. Baker et al., EFFECTS OF METALLOPROTEINASE INHIBITORS ON LEUKOTRIENE A(4) HYDROLASEIN HUMAN AIRWAY EPITHELIAL-CELLS, Biochemical pharmacology, 50(7), 1995, pp. 905-912
Human neutrophil leukotriene A(4) (LTA(4)) hydrolase is a zinc-contain
ing metalloproteinase with aminopeptidase activity and can be inhibite
d by some metalloproteinase inhibitors. Human airway epithelial cells
also contain an LTA(4) hydrolase enzyme that has some novel properties
, suggesting that this enzyme may be functionally and structurally uni
que. Thus, we questioned whether the epithelial enzyme could also be i
nhibited by metalloproteinase inhibitors. Transformed human airway epi
thelial cells were studied either intact or disrupted. Of the metallop
roteinase inhibitors examined, only captopril, bestatin, and fosinopri
lat had appreciable inhibitory activity for LTA(4) hydrolase in disrup
ted epithelial cells. Concentration-inhibition curves to captopril, be
statin, and fosinoprilat revealed IC50 values of 430 mu M, 7 mu M, and
1 mM respectively, for disrupted-cell LTA(4) hydrolase activity. In c
ontrast to its effects on neutrophils, 1,10-O-phenanthroline had no si
gnificant effect on disrupted epithelial cell hydrolase activity and h
ad only minimal effects when this activity was partially purified (179
-fold). LTA(4) hydrolase concentration-inhibition curves examined in i
ntact cells with captopril, bestatin, and 1,10-O-phenanthroline reveal
ed IC50 values of 63, 70, and 920 mu M, respectively. Aminopeptidase a
ctivity in disrupted epithelial cells was inhibited by amastatin, best
atin, and 1, 10-O-phenanthroline (IC50 values of 500 nM, 1 mu M, and 1
7 mu M, respectively), but not by captopril at the highest concentrati
on tested, 10 mM. These findings are in contrast to prior studies in n
eutrophils. When neutrophils were stimulated with A23187 after treatme
nt with captopril, transcellular synthesis of LTB(4) was inhibited mor
e effectively than direct synthesis of leukotriene B-4 (LTB(4)) (43.8
+/- 2.5 vs 18.5 +/- 4.7%; N = 8, P < 0.02). We conclude that LTA(4) hy
drolase activity of human airway epithelial cells is inhibited by some
metalloproteinase inhibitors, but that the profile of inhibition is d
istinct from that for the neutrophil enzyme. These data provide additi
onal information that LTA(4) hydrolase in the epithelial cell is a nov
el enzyme, distinct from that found in the neutrophil.