TIME COURSE OF INDUCTION OF RAT HEPATIC DRUG METABOLIZING ENZYME ACTIVITIES FOLLOWING DIETARY ADMINISTRATION OF FLAVONOIDS

Abstract

Effects of continuous feeding flavonoids (flavone, flavanone, and tangeretin) on drug-metabolizing enzymes in rat liver were investigated to ascertain how long feeding is required to reach maximal induction and to determine whether maximal induction is maintained for a long period of feeding. In the first experiment rats received a diet containing 10 mmol flavonoid/kg dry matter for 4, 8, 16, or 32 d. The second experiment was designed to examine the time course for induction during the first 4 d. The kinetics of induction depended on the chemical structure of the flavonoid and was different from one enzyme to another. Flavone increased P450 1A and P450 2B apoproteins and stimulated many enzyme activities. A significant increase of P450 1A1/2 proteins, ethoxyresorufin O-deethylase (EROD), and methoxyresorufin O-demethylase (MROD) activities occurred as early as 6 h after the first administration, and a gradual increase was observed up to 4 d of feeding. P450 2B1/2 proteins and pentoxyresorufin O-depentylase (PROD) activity were also increased but after a lag period when compared with P450 1A1/2 proteins. EROD and MROD activities declined after 4 d, whereas PROD activity remained steady during 32 d of flavone feeding. Glutathione transferase (GST) and p-nitrophenol UDP-glucuronosyl transferase (UGT) activities were also increased. The maximal induction was reached by 4 d of feeding for UGT and after a longer duration of feeding (16 d) for GST. Flavanone treatment induced mostly P450 2B1/2 proteins and PROD, GST, and UGT activites. After 4 d of feeding, P450 2B1/2 proteins and PROD activity declined whereas GST and UGT activities remained steady. Tangeretin treatment produced changes similar to flavone but of lesser magnitude and after a longer delay.