Dose-response relationships of tissue distribution and induction of CYP1A1 and CYP1A2 enzymatic activities following acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice.
Tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to be dose-dependent in rats. However, no reported studies in mice have demonstrated dose- and time-dependent distribution of TCDD and the potential sensitivities of target tissues to enzyme induction. The objectives of this study were to determine in mice the effects of dose (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg) and time (7, 14, 21, and 35 days posttreatment) on tissue distribution (18 tissues) and enzyme induction (CYP1A1 in liver, skin, and lung and CYP1A2 in liver). Distribution of TCDD-derived radioactivity in all tissues was dose- and time-dependent with nonlinear distribution. Liver-to-adipose tissue concentration ratios range from 0.6 to 3.1 (low to high dose at Day 7) demonstrating a dose-dependent shift in the disposition of TCDD. In contrast to liver, relative concentrations of percentage dose/g and percentage dose/total tissue decreased with increasing doses in all other tissues. At Day 7 and lowest dose, all tissues contained < 3% dose/g except for thyroid, adrenals, skin, liver, and adipose tissue which had 3, 6, 6, 15, and 24% dose/g, respectively. Induction of EROD activity, a marker for CYP1A1, was dose-dependent in liver, lung, and skin but did not parallel tissue concentrations of TCDD. At the highest dose, fold induction of EROD activity was two times greater in lung than liver, while the concentration in liver was 100 times greater than that in lung. Fold inductions of EROD activity in liver and skin were similar but the concentration was 20 times greater in liver than that in skin. Induction of hepatic acetanilide-4-hydroxylase (ACOH) activity, a CYP1A2 marker, was dose-dependent. Results of the present study demonstrated dose and time dependency in tissue distribution and induction of CYP1A1 and CYP1A2 as well as tissue sensitivities for enzyme induction in the female B6C3F1 mouse. These results provide important considerations for high- to low-dose extrapolations in risk assessments and use of sensitive markers of enzyme induction as surrogates for estimating exposure and in predicting risk.
Diliberto
J J
JJ
Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Akubue
P I
PI
Luebke
R W
RW
Birnbaum
L S
LS
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011897:Random Allocation; D014018:Tissue Distribution
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2