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 con taining 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 stimu lated many enzyme activities A significant increase of P450 1A1 2 proteins ethoxyre sorufin 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 maxi mal induction was reached by 4 d of feeding for UGT and after a longer duration of feed ing 16 d for GST Flavanone treatment induced mostly P450 2B1 2 proteins and PROD GST and UGT activities After 4 d of feeding P450 2B1 2 proteins and PROD activity declined whereas GST and UGT activities remained steady Tangeretin treatment pro duced changes similar to flavone but of lesser magnitude and after a longer delay