In addition to being one of the most toxic chemicals known,
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) is the most potent inducer of rat liver microsomal
cytochrome P-4501A1 (P-450c). Previous studies have demonstrated that a high affinity, low capacity cytosolic receptor (the
Ah receptor) mediates the activity of
TCDD to induce
cytochrome P-4501A1, which catalyzes
benzo[a]pyrene hydroxylation [aryl
hydrocarbon hydroxylase (AHH]) and
7-ethoxyresorufin O-dealkylation (
EROD). The results of the present study indicate that
6-methyl-1,3,8-trichlorodibenzofuran (
MCDF) effectively competes with [3H]
TCDD for binding to the
Ah receptor in rat liver cytosol. The concentration of
MCDF effecting 50% displacement of [3H]
TCDD was 4.9 X 10(-8) M, which is approximately 50 times greater than the EC50 for unlabeled
TCDD (approximately 1 X 10(-9) M). However, in contrast to
TCDD,
MCDF was only a weak inducer of AHH and
EROD activity in rat
hepatoma H-4-II cells in culture. When co-incubated,
MCDF diminished in a concentration-dependent manner the ability of
TCDD to induce AHH and
EROD activity in vitro. Treatment of rats with 20-200 mumol/kg
MCDF in vivo had little or no effect on liver microsomal AHH and
EROD activity, whereas treatment of rats with 16 nmol/kg
TCDD caused a 6- and a 70-fold induction of AHH and
EROD activity, respectively. When co-administered,
MCDF diminished by approximately 50% the ability of
TCDD to induce AHH and
EROD activity in vivo. The partial antagonism produced by 50 mumol/kg
MCDF could be partially overcome by doubling the dosage of
TCDD from 16 to 32 nmol/kg. Immunochemical analysis of rat liver microsomes revealed that treatment of rats with 20-200 mumol/kg
MCDF caused little or no induction of
cytochromes P-4501A1 and P-4501A2 (P-450d), whereas these
isozymes were induced 33- and 5-fold, respectively, in rats treated with 16 nmol/kg
TCDD. When co-administered,
MCDF diminished by approximately 50% the ability of
TCDD to induce
cytochrome P-4501A1 in vivo, which established that
MCDF was not simply acting as an inhibitor of AHH and
EROD activity.
MCDF also antagonized the ability of
TCDD to induce
cytochrome P-4501A2, which suggests that the induction of both
cytochromes P-4501A1 and P-4501A2 is regulated by the
Ah receptor. These results indicate that
MCDF binds with high affinity to the
Ah receptor in rat liver cytosol and competitively blocks the binding of
TCDD.(ABSTRACT TRUNCATED AT 400 WORDS)