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
Jj. Diliberto et al., 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, Toxicology and applied pharmacology, 130(2), 1995, pp. 197-208
Tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has b
een shown to be dose-dependent in rats. However, no reported studies i
n 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 o
f dose (0, 0.1, 1, or 10 mu g [H-3]TCDD/kg) and time (7, 14, 21, and 3
5 days posttreatment) on tissue distribution (18 tissues) and enzyme i
nduction (CYP1A1 in liver, skin, and lung and CYP1A2 in liver). Distri
bution of TCDD-derived radioactivity in all tissues was dose- and time
-dependent with nonlinear distribution. Liver-to-adipose tissue concen
tration ratios range from 0.6 to 3.1 (low to high dose at Day 7) demon
strating a dose-dependent shift in the disposition of TCDD. In contras
t to liver, relative concentrations of percentage dose/g and percentag
e dose/total tissue decreased with increasing doses in all other tissu
es. 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 ma
rker for CYP1A1, was dose-dependent in liver, lung, and skin but did n
ot parallel tissue concentrations of TCDD. At the highest dose, fold i
nduction of EROD activity was two times greater in lung than liver, wh
ile 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. Ind
uction 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 CYP1A
1 and CYP1A2 as well as tissue sensitivities for enzyme induction in t
he female B6C3F1 mouse. These results provide important considerations
for high- to low-dose extrapolations in risk assessments and use of s
ensitive markers of enzyme induction as surrogates for estimating expo
sure and in predicting risk. (C) 1995 Academic Press, Inc.