A Mechanism-Based Mathematical Model of Aryl Hydrocarbon Receptor-Mediated CYP1A Induction in Rats Using β-Naphthoflavone as a Tool Compound

Abstract

ABSTRACT:␤-Naphthoflavone (BNF) is a synthetic flavone that selectively and potently induces CYP1A enzymes via aryl hydrocarbon receptor activation. Mechanism-based mathematical models of CYP1A enzyme induction were developed to predict the time course of enzyme induction and quantitatively evaluate the interrelationship between BNF plasma concentrations, hepatic CYP1A1 and CYP1A2 mRNA levels, and CYP1A enzyme activity in rats in vivo. Male Sprague-Dawley rats received a continuous intravenous infusion of vehicle or 1.5 or 6 mg ⅐ kg ؊1 ⅐ h ؊1 BNF for 6 h, with blood and liver sampling. Plasma BNF concentrations were determined by liquid chromatography-tandem mass spectrometry. Hepatic mRNA levels of CYP1A1 and CYP1A2 were determined by TaqMan. Ethoxyresorufin O-deethylation was used to measure the increase in CYP1A enzyme activity as a result of induction. The induction of hepatic CYP1A1/CYP1A2 mRNA and CYP1A activity occurred within 2 h after BNF administration. This caused a rapid increase in metabolic clearance of BNF, resulting in plasma concentrations declining during the infusion. Overall, the enzyme induction models developed in this study adequately captured the time course of BNF pharmacokinetics, CYP1A1/CYP1A2 mRNA levels, and increases in CYP1A enzyme activity data for both dose groups simultaneously. The model-predicted degradation half-life of CYP1A enzyme activity is comparable with previously reported values. The present results also confirm a previous in vitro finding that CYP1A1 is the predominant contributor to CYP1A induction. These physiologically based models provide a basis for predicting druginduced toxicity in humans from in vitro and preclinical data and can be a valuable tool in drug development.

Induction of xenobiotic-metabolizing enzymes in hepatocytes by beta-naphthoflavone: Time-dependent changes in activities, protein and mRNA levels

“…ing a 24-h exposure of hepatocytes to BNF and all tested parameters correlated well. The response to BNF in hepatocytes was in agreement with the observation that the induction of hepatic CYP1A1/CYP1A2 mRNA and CYP1A activity in rats in vivo occurred within 2 h after BNF administration (22). A good correlation between the induction of CYP1A1/2 enzyme activities and mRNA expression in human hepatocytes has been also reported (4).…”

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

“…In order to examine if AhR ligands which activates the canonical AhR pathway demonstrate selective modulation, differential gene expression elicited TCDD, PCB126, β-naphthoflavone (βNF), and indolo-[3,2b]-carbazole (ICZ) was examined in mouse Hepa1c1c7 cells and C57BL/6 liver samples. Although each ligand exhibits high AhR binding affinity, Cyp1a1 mRNA induction and the induction of aryl hydrocarbon hydroxylase activity (Boobis et al, 1977; Chen et al, 1995, 2010; Denison and Nagy, 2003; Denison et al, 2011; Kopec et al, 2008; Pohjanvirta et al, 2002), they are structurally diverse with different metabolism kinetics. Therefore, global gene expression profiles were compared not only to identify conserved differential expression but also to investigate divergent and ligand-specific gene expression changes suggestive of SAhRM activity.…”

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone

“…It has previously been shown that the plasma concentration of BNF reaches a maximal level at 80-120 min and then starts declining toward a lower plateau value in SD rats given a continuous intravenous infusion of 1.5 or 6 mg/kg/hr BNF for 6 hr (Chen et al, 2010). BNF is known as a substrate of CYP1A enzymes and the BNF clearance increases with time after continuous intravenous infusion to rats (Chen et al, 2010). Such a time-dependent increase in clearance supports the present finding of plasma BNF concentrations not being detected in BNF treated rats.…”

“…This finding suggests that the induction of liver drug-metabolizing enzyme by BNF may affect the metabolism of OPZ in the OPZ+BNF group. It has previously been shown that the plasma concentration of BNF reaches a maximal level at 80-120 min and then starts declining toward a lower plateau value in SD rats given a continuous intravenous infusion of 1.5 or 6 mg/kg/hr BNF for 6 hr (Chen et al, 2010). BNF is known as a substrate of CYP1A enzymes and the BNF clearance increases with time after continuous intravenous infusion to rats (Chen et al, 2010).…”