Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs.
- Author:
Kooil KANG
1
;
Sung Jun BAE
;
Woo Mi KIM
;
Dae Heui LEE
;
Un Suck CHO
;
Mu Sang LEE
;
Myung Huck LEE
;
Sang Il NAM
;
Klaus E KUETTNER
;
David E SCHWARTZ
Author Information
1. Department of Pharmacology, Kosin University Medical College, Pusan, Korea. kooil1@hotmail.com
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
- Keywords:
NSAIDs;
human neutrophil elastase;
inflammatory diseases;
Raman shifts
- MeSH:
Anti-Inflammatory Agents, Non-Steroidal/pharmacology*;
Chromatography, Affinity;
Computer Simulation;
Enzyme Inhibitors/pharmacology;
Human;
Isoenzymes/isolation & purification;
Isoenzymes/antagonists & inhibitors;
Ketoprofen/pharmacology;
Leukocyte Elastase/isolation & purification;
Leukocyte Elastase/antagonists & inhibitors*;
Models, Molecular;
Naproxen/pharmacology;
Phenylbutazone/analogs & derivatives;
Salicylates/pharmacology;
Spectrum Analysis, Raman
- From:Experimental & Molecular Medicine
2000;32(3):146-154
- CountryRepublic of Korea
- Language:English
-
Abstract:
Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.
