Effect of 1,2,4-trichlorodibenzo-p-dioxin on drug-metabolizing enzymes in the rat liver.

The effects of 1,2,4-trichlorodibenzo-p-dioxin (1,2,4-TrCDD) on drug-metabolizing-enzymes have been studied in male Wistar rats. 1,2,4-TrCDD (0.1 mmol/kg per day) was administered by i.p. injection for 3 days. Among the cytochrome P-450 (P450)-mediated monooxygenase activities tested, 7-ethoxyresorufin O-deethylase, which is associated with CYP1A1, was remarkably induced by 1,2,4-TrCDD (0.1 mmol/kg). The relative induction to control activity was 32.9-fold. Also, 1,2,4-TrCDD increased other CYP1A-mediated monooxygenase activities such as 7-ethoxycoumarin O-deethylase, 4-nitroanisole O-demethylase, 7-methoxyresorufin O-demethylase and caffeine N-demethylase from 5.7- to 1.9-fold. Western immunoblotting showed that the levels of CYP1A1 and CYP1A2 proteins in liver microsomes were increased by 1,2,4-TrCDD. On the other hand, 7-pentoxyresorufin O-depentylase activity was induced 2.6-fold whereas aniline 4-hydroxylase, nitrosodimethylamine N-demethylase and erythromycin N-demethylase activities were increased slightly (1.3-, 1.6- and 1.3-fold, respectively) by 1,2,4-TrCDD. However, aminopyrine N-demethylase was not significantly induced by 1,2,4-TrCDD. Of the Phase II drug-metabolizing enzymes, DT-diaphorase and glutathione S-transferase (GST) activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and those of UDP-glucuronyltransferase (UGT) towards 4-nitrophenol and 7-hydroxycoumarin were increased from 2.7 to 1.4-fold by 1,2,4-TrCDD. These results indicate that 1,2,4-TrCDD induces both Phase I and Phase II drug-metabolizing enzymes in the rat liver.