MODULATING EFFECTS OF THYROID STATE ON THE INDUCTION OF BIOTRANSFORMATION ENZYMES BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

In this study we investigated to what extent the induction of detoxifi cation enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is modula ted by concomitant TCDD-induced changes in thyroid state. Euthyroid (E u) male Sprague-Dawley rats, surgically thyroidectomized (Tx) rats and Tx rats receiving substitution doses of 3,3',5-triiodothyronine (Tx T3) or thyroxine (Tx + T4) by osmotic minipumps were treated with a s ingle ip injection of 10 mu g TCDD/kg/bwt or with vehicle (corn oil). Three days after TCDD administration, rats were sacrificed and blood a nd livers were collected for analysis. Total hepatic cytochrome P450 ( CYP) content was increased by approximate to 50% by TCDD in all groups but was not affected by thyroid state. In Eu rats, TCDD increased CYP 1A1/1A2 activity 90-fold, CYP1A1 protein content 52-fold and CYP1A1 mR NA levels approximate to 5.8-fold. Similar findings were obtained in T x, Tx + T3 and Tx + T4 rats except that TCDD-induced CYP1A1 activity w as significantly decreased in Tx rats. NADPH cytochrome P450 reductase activity was not affected by TCDD but was decreased in Tx rats, which may explain the diminished TCDD-induced CYP1A1 activity in Tx rats. H epatic p-nitrophenol UDP-glucuronyltransferase (UGT) activity was indu ced approximate to 4-fold by TCDD in Eu rats. Similar basal and TCDD-i nduced activities were observed in Tx + T3 and Tx + T4 rats, but TCDD- induced activities were significantly lower in Tx rats. TCDD did not h ave a significant effect on overall glutathione-S-transferase (GST) ac tivity or hepatic GST 2-2, 3-3 or 4-4 protein levels but produced a ma rked increase in GST 1-1 protein levels. Thyroid state did not affect basal or TCDD-induced GST activity or subunit pattern. Iodothyronine s ulfotransferase (ST) activity was not affected by TCDD treatment and w as slightly but not significantly lower in Tx rats than in Eu, Tx + T3 and Tx + T4 rats. These results suggest that the changes in thyroid h ormone levels associated with TCDD treatment have little modulating ef fects on the induction of hepatic detoxification enzymes in Sprague-Da wley rats exposed to this compound. (C) 1998 Elsevier Science Ireland Ltd.