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Titolo:
Kinetic basis for selective inhibition of cyclo-oxygenases
Autore:
Gierse, JK; Koboldt, CM; Walker, MC; Seibert, K; Isakson, PC;
Indirizzi:
Monsanto Searle Discovery Res, Chesterfield, MO 63198 USA Monsanto Searle Discovery Res Chesterfield MO USA 63198 eld, MO 63198 USA
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 339, anno: 1999,
parte:, 3
pagine: 607 - 614
SICI:
0264-6021(19990501)339:<607:KBFSIO>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROSTAGLANDIN-G/H SYNTHASE-1; TIME-DEPENDENT INHIBITION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ANTI-INFLAMMATORY DRUGS; CYCLOOXYGENASE COX-2; MESSENGER-RNA; IN-VITRO; ASPIRIN; ACID; EXPRESSION;
Keywords:
celecoxib; inhibitors; prostaglandin synthase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Gierse, JK Monsanto198arle Discovery Res, 700 Chesterfield Pkwy N, Chesterfield, MO 63 Monsanto Searle Discovery Res 700 Chesterfield Pkwy N Chesterfield MO USA 63198
Citazione:
J.K. Gierse et al., "Kinetic basis for selective inhibition of cyclo-oxygenases", BIOCHEM J, 339, 1999, pp. 607-614

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics onCOX-1 (K-i = 10-16 mu M). An initial competitive interaction with COX-2 can also be discerned with celecoxib (K-i = 11-15 mu M), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (K-inact = 0.03-0.5 s(-1)). Half-maximal inhibition (IC50) using endpoint assays reflects the competitive component on COX-1 (IC50 = 4-19 mu M) and the inactivation component on COX-2 (IC50 = 0.003-0.006 mu M). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with thisclass is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-I and COX-2 using IC50 ratios of questionable validity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/08/20 alle ore 23:35:18