Differential activation of CYP2C9 variants by dapsone.


:Studies have shown that CYP2C9.1 mediated metabolism of flurbiprofen or naproxen is activated by co-incubation with dapsone. However, dapsone activation has not been examined in the known variant forms of CYP2C9. Six concentrations of flurbiprofen (2-300microM) or naproxen (10-1800 microM) were co-incubated with six concentrations of dapsone (0-100 microM) and with reconstituted, purified CYP2C9.1, CYP2C9.2 (R144C), CYP2C9.3 (I359L), or CYP2C9.5 (D360E), in order to assess degrees of activation. Dapsone increased the efficiency (V(m)/K(m)) of flurbiprofen 4'-hydroxylation by CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5 by 8-, 31-, 47-, and 22-fold, respectively. In similar experiments using the substrate naproxen, dapsone increased the efficiency of naproxen demethylation 7-, 15-, 13-, and 22-fold, in CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5, respectively. Also, dapsone normalized naproxen's kinetic profile from biphasic (CYP2C9.1 and CYP2C9.2) or linear (CYP2C9.3 and CYP2C9.5) to hyperbolic for all variant forms. Thus, amino acid substitutions of CYP2C9 variants affect the degree of dapsone activation in a genotype-dependent fashion. Furthermore, the degree of effect noted across variants appeared to be dependent on the substrate studied.


Biochem Pharmacol


Biochemical pharmacology


Hummel MA,Dickmann LJ,Rettie AE,Haining RL,Tracy TS




Has Abstract


2004-05-15 00:00:00














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    authors: Penning TM

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    pub_type: 杂志文章


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    pub_type: 杂志文章


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