Further Differentiation of 2'- and 4'-Chloroflavones as Inducers of Hepatic Microsomal Monooxygenases in Rats

Abstract

2'-Chloroflavone (CF) and 4'-CF were studied as inducers of cytochrome P-450-mediated monooxygenases in rat hepatic microsomes by comparison with phenobarbital (PB) and 3-methylcholanthrene (MC). As a result of interaction with the substrate 7-ethoxycoumarin (7-EC), 2'-CF-induced microsomes showed a difference spectrum different from usual type I, whereas 4'-CF-induced microsomes showed a typical type I spectrum. 2'-CF-induced microsomes increased the V_max of aminopyrine (AM) N-demethylase activity about 1.6-fold while not affecting the apparent K_m value. In contrast, 4'-CF-induced microsomes decreased the K_m of 7-EC O-deethylase activity to about one fourth while significantly increasing the V_max value. All the activities of AM N-demethylase, 7-EC O-deethylase and 6, 7-dimethoxycoumarin O-demethylase in 2'-CF-induced microsomes were inhibited strongly by metyrapone and SKF 525-A, and significantly by diphenhydramine. The three enzyme activities in 4'-CF-induced microsomes were inhibitied markedly by α-naphthoflavone and significantly by 2-bromo-4'-nitroacetophenone. These results further support the previous proposal that 2'-CF is a PB-type inducer of cytochrome P-450 while 4'-CF is a MC-type inducer.