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Titolo:
Dapsone activation of CYP2C9-mediated metabolism: Evidence for activation of multiple substrates and a two-site model
Autore:
Hutzler, JM; Hauer, MJ; Tracy, TS;
Indirizzi:
W Virginia Univ, Sch Pharm, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA W Virginia Univ Morgantown WV USA 26506 eut Sci, Morgantown, WV 26506 USA Pharmacia Inc, Global Metab & Invest Sci, Kalamazoo, MI USA Pharmacia IncKalamazoo MI USA bal Metab & Invest Sci, Kalamazoo, MI USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 7, volume: 29, anno: 2001,
pagine: 1029 - 1034
SICI:
0090-9556(200107)29:7<1029:DAOCME>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; HYDROXYLAMINE METABOLITES; O-DEMETHYLATION; ACTIVE-SITE; KINETICS; BINDING; 2C9; RAT; 4'-HYDROXYLATION; COOPERATIVITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
23
Recensione:
Indirizzi per estratti:
Indirizzo: Tracy, TS W Virginia Univ, Sch Pharm, Dept Basic Pharmaceut Sci, HSN POB 9530, Morgantown, WV 26506 USA W Virginia Univ HSN POB 9530 Morgantown WV USA 26506 V 26506 USA
Citazione:
J.M. Hutzler et al., "Dapsone activation of CYP2C9-mediated metabolism: Evidence for activation of multiple substrates and a two-site model", DRUG META D, 29(7), 2001, pp. 1029-1034

Abstract

Dapsone activates CYP2C9-mediated metabolism in various expression systemsand is itself metabolized by CYP2C9 to its hydroxylamine metabolite. Studies were conducted with expressed CYP2C9 to characterize the kinetic effectsof dapsone (0-100 muM) on (S)-flurbiprofen (2-300 muM), (S)-naproxen (10-1800 muM), and piroxicam (5-900 muM) metabolism in 6 x 6 matrix design experiments. The influence of (S)-flurbiprofen on dapsone hydroxylamine formation was also studied. Dapsone increased the Michaelis-Menten-derived V-max offlurbiprofen 4'-hydroxylation from 12.6 to 20.6 pmol/min/pmol P450, and lowered its K-m from 28.9 to 10.0 muM, suggesting that dapsone activates CYP2C9-mediated flurbiprofen metabolism without displacing flurbiprofen from the active site, supporting a two-site model describing activation. Similar results were observed with piroxicam 5'-hydroxylation, as V-max was increased from 0.08 to 0.20 pmol/min/pmol P450 and K-m was decreased from 183 to 50muM in the presence of dapsone. In addition, the kinetic profile for naproxen was converted from biphasic to hyperbolic in the presence of dapsone, while exhibiting similar decreases in K-m and increases in V-max. Kinetic parameters were also estimated using the two-site binding equation, with cu values <1 and <beta> values >1, indicative of activation. Additionally, dapsone hydroxylamine formation was measured from incubations containing flurbiprofen, exhibiting a kinetic profile that was minimally affected by the presence of flurbiprofen. Overall, these results suggest that dapsone activates the metabolism of multiple substrates of CYP2C9 by binding within the active site and causing positive cooperativity, thus lending further support to a two-site binding model of P450-mediated metabolism.

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Documento generato il 25/01/20 alle ore 06:31:14