Steric and electronic requirements for chloroflavone congeners as hepatic microsomal monooxygenase inducers.
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 Hückel 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 (ELUMO) and the difference (delta E) between ELUMO and HOMO energy for the congeners. The ELUMO and delta E 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.
Yamamoto
K
K
Department of Chemistry, Hokuriku University, Kanazawa, Japan.
Kato
S
S
D020003:1-Octanol; D000818:Animals; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D000442:Octanols / Q000737:chemistry; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D005419:Flavonoids; D000442:Octanols; D014867:Water; D003577:Cytochrome P-450 Enzyme System; D010090:Oxidoreductases, O-Demethylating; C083062:scoparone O-demethylase; D020003:1-Octanol