Effects of bioflavonoids on hepatic P450 activities

Abstract

1. The effects of tangeretin, green tea flavonoids, and other flavonoids on 7-ethoxyresorufin-O-deethylase (EROD; 450 1A), 7-pentoxyresorufin-O-dealkylase (PROD; P450 2B), p-nitrophenol hydroxylase (PNPH, P450 2E1), and erythromycin-N-demethylase (ERDM; P450 3A) were examined in induced rat liver microsomes. EROD, PNPH, ERDM, and nifedipine oxidase (NIFO; P450 3A4) were examined in human liver microsomes. 2. All flavonoids tested inhibited EROD activity at higher concentrations in liver microsomes. Flavone and tangeretin were potent inhibitors of EROD, with IC50's of 0.7 and 0.8 microM respectively in rat liver microsomes and 0.15 and 16 microM respectively in human liver microsomes. The green tea flavonoid (-)-epicatechin-3-gallate (ECG) was the most potent inhibitor of EROD in human liver microsomes (IC50 = 75 microM). The effect of the green tea flavonoids on EROD was complex; in addition to inhibition at high concentrations of flavonoid, moderate activation was seen at lower concentrations. 3. 450 2B-, 2E1- and 3A-dependent activities in rat and human liver microsomes were only moderately inhibited by any of the flavonoids tested, and, in general, ECG was the most potent inhibitor for these activities with IC50's ranging from 75 to 300 microM. 4. Tangeretin inhibited EROD activity (P450 1A2) in human liver microsomes in a competitive manner with a Ki = 68 nM. Tangeretin inhibited NIFO activity (P450 3A4) in human liver microsomes in an uncompetitive manner with Ki = 72 microM.

Negundoside, an irridiod glycoside from leaves of Vitex negundo , protects human liver cells against calcium-mediated toxicity induced by carbon tetrachloride

“…Results in this study indicate that NG does not affect p-nitrophenol metabolism by CYP2E1 in liver microsomes under the experimental conditions ( Figure 5 A and B); therefore, the mechanism by which NG affords its protection is not by inhibition of CYP2E1 activity. This is in confirmation to earlier reports in which many plant derived products like, Scutellariae radix [40] , Humulus lupulus [41] , green tea compounds [42] have also been shown to be hepatoprotective in other systems without any effect on CYP2E1 catalytic activity.…”

Potent Modification of Inducible CYP1A1 Expression by Flavonoids

“…We observed EROD activity to be inhibited in the presence of flavone in mouse hepatocytes, although the induction of CYP1A1 mRNA and protein expression was prominent. The same inhibitory effect of flavone was reported in human liver microsomes by Obermeier et al 34) Therefore, whether EROD activity is induced or inhibited might depend on the enzyme source or culture system, and these observations again indicate the necessity for a rational explanation of the discrepancy in results regarding the effects of flavonoids on metabolizing enzymes.…”

Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants

“…The activity of some P450s are either induced or inhibited by¯avonoids. For example, naringenin and tangeretin are potent inhibitors of microsomal 7-ethoxyresoru®n-O-deethylase (EROD) activity, which is a marker substrate for P450 1A (Obermeier et al 1995). Similarly, quercetin inhibits EROD activity (IC 50 < 1 mM) in microsomes from human hepatoma HepG2 cells (Musonda et al 1997).…”

“…Pentoxyresoru®n-O-dealkylase (PROD) activity is also decreased, indicating ability of the¯avonoids to inhibit P450 2B activity. Tangeretin inhibits nifedepine oxidase, (P450 3A) in human liver microsomes (Obermeier et al 1995). Flavone and several hydroxylated derivatives (3-OH-, 5-OH-, 7-OH-and 3,7-dihydroxy¯avone) are potent inhibitors of cDNA-expressed human P450s 1A1 and 1A2 (IC 50 < 1 mM), while galangin is a selective inhibitor of P450 1A2 (Zhai et al 1998).…”