Oxidative hydrolysis of scoparone by cytochrome P450CYP2C29 reveals a novel metabolite

Regioselective 7-demethylation of scoparone is regularly employed as an ind icator of phenobarbital-like induction of rat liver cytochrome P450 isoform CYP2B1, e,g,, by the antiepileptic drug phenytoin, After induction with ph enobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was identified in mouse liver microsomes. Cyp2c29-dependent 6-demethylation of scoparone resulted in the formation of isoscopoletin, an intermediate whic h is susceptible to further oxidation, This subsequent oxidation was also c atalyzed by Cyp2c29 with a K-m of 30,31 muM and a V-max of 3,41 muM/min . m uM P450, and resulted in the formation of the new metabolite 3-[4-methoxy-p -(3,6)-benzoquinone]-2-propenoate. This novel metabolite is the product of two consecutive oxidation reactions, proceeding over isoscopoletin to a put ative lactone which is accessible to immediate hydrolysis, due to the onium character of the ring oxygen. This opening of the lactone ring corresponds to an oxidative hydrolysis. Differential oxidation of scoparone can be use d as a sensitive indicator for distinguishing between different cytochrome P450 isoforms, (C) 2001 Academic Press.