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To investigate the effect of fluorine substitution on tolbutamide (TB) hydroxylation catalyzed by CYP2C9, the hydroxylation of TB and its fluorinated derivative 3'-fluoro-tolbutamide (3'-F-TB) by recombinant human CYP2C9*1, CYP2C9*2, and CYP2C9*3 was analyzed. In general, fluorine substitution near the metabolic site may decrease enzymatic oxidation owing to its electron-withdrawing nature. Fluorine substitution reduced the Michaelis-Menten-derived K m of 4'-hydroxylation of TB catalyzed by CYP2C9*1 from 115 (TB) to 77 (3'-F-TB) µM. In the case of TB hydroxylation catalyzed by CYP2C9*2, the K m value of TB was also reduced by fluorine substitution from 129 to 88 µM. The greatest effect of fluorine substitution on the K m in TB hydroxylation was observed in the catalysis by CYP2C9*3, in which the K m value decreased from 287 to 117 µM. When a mixture containing TB and 3'-F-TB was hydroxylated by CYP2C9, the hydroxylated metabolite ratio in CYP2C9*3 was significantly increased compared with that in CYP2C9*1 and CYP2C9*2 (p &lt; 0.01, Tukey-Kramer test). These results suggest that obtaining the metabolite profiles of fluorine-substituted analogs of the key substrate molecule may be useful as a new tool for phenotyping polymorphic CYP isoforms.

Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide