Comparison of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, a Potent Inducer of Aryl Hydrocarbon Hydroxylase, with 3-Methylcholanthrene

Abstract

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the induction of microsomal oxygenase were studied in the rat. TCDD was 3 x 104 times more potent than 3-methylcholanthrene (MC) as an inducer of hepatic aryl hydrocarbon hydroxylase. Half-maximal induction occurred at a dose of 0.85 nmole/kg. TCDD and MC produced parallel log dose-response curves for the induction of hepatic aryl hydrocarbon hydroxylase, with the same maximal response. The simultaneous administration of maximally inducing doses of both drugs produced no greater response than either drug alone. TCDD, like MC, induced a spectrally distinct type of cytochrome P-450, with a shift in the absorption maximum of the carbon monoxide difference spectrum from 450 nm to 448 nm, and an increase in the ratio of the 455 nm:430 nm absorption maxima of the ethyl isocyanide difference spectra. Following a single dose of TCDD (31.1 nmoles/kg), hepatic aryl hydrocarbon hydroxylase activity and microsomal hemoprotein remained elevated for over 35 days. Both TCDD and MC had little effect on hepatic aminopyrine N-demethylase and NADPH-cytochrome c reductase. The dose of TCDD which produced half-maximal induction of hepatic aryl hydrocabon hydroxylase in the rat, chick embryo, and several strains of mice was similar, varying from 0.4 to 1.2 nmoles/kg.