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Titolo:
EFFECT OF INHIBITOR TIME-DEPENDENCY ON SELECTIVITY TOWARDS CYCLOOXYGENASE ISOFORMS
Autore:
OUELLET M; PERCIVAL MD;
Indirizzi:
MERCK FROSST CTR THERAPEUT RES,DEPT BIOCHEM & MOLEC BIOL,POB 1005 POINTE CLAIRE PQ H9R 4P8 CANADA MERCK FROSST CTR THERAPEUT RES,DEPT BIOCHEM & MOLEC BIOL POINTE CLAIRE PQ H9R 4P8 CANADA
Titolo Testata:
Biochemical journal
, volume: 306, anno: 1995,
parte:, 1
pagine: 247 - 251
SICI:
0264-6021(1995)306:<247:EOITOS>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROSTAGLANDIN ENDOPEROXIDE SYNTHASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ANTI-INFLAMMATORY DRUGS; SWISS 3T3 CELLS; INDUCIBLE CYCLOOXYGENASE; EXPRESSION; BIOSYNTHESIS; INDOMETHACIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
28
Recensione:
Indirizzi per estratti:
Citazione:
M. Ouellet e M.D. Percival, "EFFECT OF INHIBITOR TIME-DEPENDENCY ON SELECTIVITY TOWARDS CYCLOOXYGENASE ISOFORMS", Biochemical journal, 306, 1995, pp. 247-251

Abstract

Cyclooxygenase (Cox) is a key enzyme in the biosynthesis of prostaglandins and, as such, is the target of non-steroidal antiinflammatory drugs (NSAIDs). Two isoforms exist, being expressed consitutively (Cox-1), or inducibly in response to inflammatory mediators (Cox-2). Currently available NSAIDs inhibit both isoforms somewhat equipotently but selective Cox-2 inhibition may eliminate unwanted side effects. We have characterized the kinetic mechanisms of the interactions of purified recombinant human cyclooxygenase-1 and -2 (hCox-1, hCox-2) with the selective Cox-2 inhibitor (2-cyclohexyloxy-4-nitrophenyl)methanesulphonamide (NS-398) and some classical non-selective NSAIDs. NS-398, flurbiprofen, meclofenamic acid and indomethacin are time-dependent, irreversible inhibitors of hCox-2. The inhibition is consistent with a two-stepprocess, involving an initial rapid equilibrium binding of enzyme andinhibitor, characterized by K-i, followed by the slow formation of a tightly bound enzyme-inhibitor complex, characterized by a first-orderrate constant k(on). NS-398 is a time-independent inhibitor of hCox-1, consistent with the formation of a reversible enzyme-inhibitor complex. Flurbiprofen, meclofenamic acid and indomethacin are also time-dependent inhibitors of hCox-1 and hence show little selectivity for one isoform over the other. Flufenamic acid is time independent towards both isoforms and is also non-selective. The high degree of selectivity of NS-398 towards Cox-2 results therefore from the difference in the nature of the time-dependency of inhibition of the two isoforms.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 04:33:18