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

Effects of continuous feeding flavonoids (flavone, flavanone, and tang eretin) 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 perio d 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 expe riment was designed to examine the time course for induction during th e first 4 d. The kinetics of induction depended on the chemical struct ure of the flavonoid and was different from one enzyme to another. Fla vone increased P450 1A and P450 2B apoproteins and stimulated many enz yme activities. A significant increase of P450 1A1/2 proteins, ethoxyr esorufin 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 p roteins and pentoxyresorufin O-depentylase (PROD) activity were also i ncreased but after a lag period when compared with P450 1A1/2 proteins . EROD and MROD activities declined after 4 d whereas PROD activity re mained 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 feedi ng for UGT and after a longer duration of feeding (16 d) for GST. Flav anone treatment induced mostly P450 2B1/2 proteins and PROD, GST, and UGT activities. After 4 d of feeding, P450 2B1/2 proteins and PROD act ivity declined whereas CST and UGT activities remained steady. Tangere tin treatment produced changes similar to flavone but of lesser magnit ude and after a longer delay.