In vitro and in vivo effects of naringin on cytochrome P450-dependent monooxygenase in mouse liver

In vitro and in vivo effects of naringin on microsomal monooxygenase were s tudied to evaluate the drug interaction of this flavonoid. In vitro additio n of naringin up to 500 mu M had no effects on benzo(a)pyrene hydroxylase ( AI-IH) activity of mouse liver microsomes. In contrast, the aglycone naring enin at 300 to 500 mu M decreased AHH activity by 50 % to 60 %. Analysis of Lineweaver-Burk and Dixon plots indicated that naringenin competitively in hibited AHH activity with an estimated Ki of 39 mu M. Naringenin at 100 mu M also reduced metabolic activation of benzo(a)pyrene to genotoxic products as monitored by umuC gene expression response in Salmonella typhimurium TA 1535/pSK1002. Tn the presence of equimolar naringenin and benzo(a)pyrene, u muC gene expression presented as beta-galactosidase activity was reduced to a level similar to the control value. Administration of a liquid diet cont aining 10 mg/ml naringin for 7 days caused 38 % and 49 % decreases of AHH a nd 7-methoxyresorufin O-demethylase activities, respectively. In contrast, the administration had no effects on cytochrome P450 (P450)-catalyzed oxida tions of 7-ethoxyresorufin, 7-ethoxycoumarin, N-nitrosodimethylamine, nifed ipine, erythromycin and testosterone. Microsomal P450 and cytochrome bg con tents and NADPH-P450 reductase activity were not affected. Immunoblot analy sis using MAb 1-7-1, which immunoreacted with both P450 1A1 and 1A2, reveal ed that the level of P450 1A2 protein was decreased by 38 %. These results demonstrate that naringenin is a potent inhibitor of AHH activity in vitro and naringin reduces the P450 1A2 protein level in vivo. These effects may indicate a chemopreventive role of naringin against protoxicants activated by P450 1A2.