Steric and Electronic Requirements for Chloroflavone Congeners as Hepatic Microsomal Monooxygenase Inducers

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We previously classified chloroflavone congeners into 3-methylcholanthrene (MC)-type, phenobarbital (PB)-type and mixed (MC plus PB)-type inducers of hepatic microsomal monooxygenases in rats. In the present study, we examined the structure-activity relationship involved in the capability of congeners to induce the described regioselective O-demethylation activity of scoparone. The steric and electronic parameters of congeners were calculated by the MM2 molecular mechanics and Extended Huckel MO methods, respectively. The molecular rectangle-area/depth ratios related well to the ratios of scoparone 6-/7-O-demethylation activities induced by the congeners. The molecular dimensions characterized the MC-type congeners as nearly planar molecules and the PB-type congeners as bulky and nonplanar. Moreover, the ratio of scoparone 6-/7-O-demethylation activities had significant correlation with both the LUMO energy (E_LUMO) and the difference (ΔE) between E_LUMO and HOMO energy for the congeners. The E_LUMO and ΔE were less in the MC-type congeners than in the PB-type. These correlations suggest that the steric and electronic features of chloroflavone congeners are responsible for the induction of cytochrome P450 isozymes and associated monooxygenase activities.