Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A2 inhibitors

Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sP...

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Bibliographic Details
Published in:European journal of pharmacology 1996-07, Vol.308 (2), p.195-204
Main Authors: FOX, N, SONG, M, DRAHEIM, S. E, BOBBITT, J. L, FISHER, L, MIHELICH, E. D, SCHREMENTI, J, SHARP, J. D, WHITE, D. L, SNYDER, D. W, HARTLEY, L. W, CARLSON, D. G, BACH, N. J, DILLARD, R. D
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Northern
Bones, joints and connective tissue. Antiinflammatory agents
Enzyme Inhibitors - pharmacology
Enzyme-Linked Immunosorbent Assay
Female
Humans
Indoles - pharmacology
Male
Medical sciences
Mice
Mice, Transgenic
Pharmacology. Drug treatments
Phospholipases A - analysis
Phospholipases A - antagonists & inhibitors
Phospholipases A - genetics
Phospholipases A2
Testis - chemistry
Testis - pathology
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Summary:Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA2 minigene. High levels of sPLA2 were detected in several tissues by immunofluorescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid LY311727), a potent new inhibitor of phospholipase A2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.
ISSN:0014-2999
1879-0712
DOI:10.1016/0014-2999(96)00257-9