Cytochrome P450-dependent alkoxyphenoxazone dealkylase activities in lung microsomes from untreated and beta-naphthoflavone-treated rats: effect of in vitro inhibitors.
Res Commun Chem Pathol Pharmacol 1987 Sep; 57(3):375-387
The reactivity of alkoxyphenoxazone dealkylase activities toward alkoxyphenoxazone derivatives was studied in-vitro. Male Sprague- Dawley-rats were injected intraperitoneally with 0 or 80mg/kg beta- naphthoflavone (6051872) (BNF). Forty eight hours later, rats were killed, the lungs were removed, and the microsomal fraction was isolated. The effects on microsomal ethoxyphenoxazone-dealkylase (EtOPhase), benzyloxyphenoxazone-dealkylase (BzOPhase), methoxyphenoxazone-dealkylase (MeOPhase), and pentoxyphenoxazone- dealkylase (PeOPh) activities were determined by measuring the rates of dealkylation of the respective oxyphenoxazones. BNF stimulated EtOPHase and MeOPhase activity, but had no effect on or slightly inhibited BzOPh and PeOPH. To determine if dealkylation of the substrates represented similar or different classes of cytochrome- P450, microsomes from BNF pretreated rats were incubated with alpha- naphthoflavone (604591) or metyrapone (54364). The extent of inhibition of EtOPHase and BzOPhase was determined. The concentrations for 50 percent inhibition (I50) of EtOPhase were 3.8x10(-8) molar (M) for alpha-naphthoflavone and 7.6x10(-5)M for metyrapone. The I50 for inhibition of BzOPhase by metyrapone was 1.0x10(-6)M. An I50 for inhibition of BzOPhase by alpha- naphthoflavone could not be determined because of the insolubility of alpha-naphthoflavone. The authors suggest that EtOPhase and MeOPhase represent polycyclic aromatic hydrocarbon (PAH) inducible forms of the cytochrome-P450 dependent alkoxyphenoxazone-O- dealkylase system. BzOPhase and PeOPhase represent non PAH inducible forms.
NIOSH-Author; Enzyme-activity; Enzyme-complexes; In-vitro-studies; Laboratory-animals; Dose-response; Microsomal-enzymes; Physiological-chemistry; Flavones
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Research Communications in Chemical Pathology and Pharmacology