In this study, we examined the effects of nobiletin, a polymethoxyflavonoid derived from Citrus depressa, on cytochrome P450 (CYP, P450) activity in the livers of dams maternally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Pregnant Wistar rats received TCDD (1 mg/kg, p.o.) on gestational day 15 (GD15), and at GD20, we examined hepatic P450 activity and its inducibility by TCDD. Ethoxyresorfin-O-deethylase (EROD) activity, a marker activity of CYP1A1, was found to be significantly induced in TCDD-treated rats, whereas although CYP1A2 activity also increased by TCDD, the effect was less pronounced than that observed for CYP1A1. In contrast, CYP3A and CYP2C6 activities were significantly higher in the TCDD group than in the control group. These results suggest that maternal exposure to TCDD elicits changes in the levels of drug-metabolizing enzyme activities, including those of CYP1A1, CYP3A, and CYP2C6. To examine the effect of nobiletin, P450-dependent activity was assayed in vitro in the presence or absence of this flavonoid. Although the effects differed depending on P450 isoform, nobiletin exhibited inhibitory effects on CYP1A1, CYP1A2, CYP2C6, and CYP3A. We accordingly anticipate that nobiletin will reduce the adverse effects of maternal exposure to TCDD via its modulatio n of P450 activity.
