The effects of topical pretreatment of CF1-Swiss mice with
TCDD on the
carcinogenesis induced by DMBA were studied. We also determined the intrinsic features of DMBA as an aryl
hydrocarbon hydroxylase (AHH) inducer through either its binding ability to
Ah receptor or its inducing effects on
benzo(a)pyrene (BP)
hydroxylase or
DMBA hydroxylase. DMBA is a poor
ligand of the
Ah receptor (26-fold and 4.3-fold weaker than
3-methylcholanthrene and BP respectively) and a very weak AHH inducer (ten million-fold weaker than
TCDD). Nevertheless, DMBA induces a specific
isozyme of
cytochrome P-450 1A1 since, for an equal dose administered to C57BL/6 mice (200 mg/kg
body weight), the
DMBA-hydroxylase activity was 1.72-fold increased by DMBA while it remained unchanged after BP treatment. In contrast, the BP-
hydroxylase activity was 1.91-fold increased by BP and only 1.47-fold by DMBA. A dose-dependent relationship exists between the increasing dose of
TCDD (from 0.001 to 1 microg per mouse) applied to mouse skin and the induction of AHH activity of skin microsomes (from 1 to 60-fold increase). For
carcinogenesis experiments, mice were either untreated or pretreated with single different doses of
TCDD and, after 24h, DMBA (10 or 25 microg per mouse) was applied to the skin. The average number of
papillomas per mouse was dependent on 1) the dose of DMBA and 2) the metabolic capacity of the skin. For 10 microg DMBA, the
TCDD only exerts an
anticarcinogenic effect (from 5.5 to 0.6
tumor per mouse) whereas for 25 microg DMBA,
TCDD exerts a dual effect: first, a cocarcinogenic effect (from 6.2 to 9 and 11.5
tumors per mouse for 0.001 and 0.01 microg
TCDD respectively) then an
anticarcinogenic effect (2.3 and 1.5
tumors per mouse for 0.1 and 1 microg
TCDD respectively). The discussion underlines the decisive importance of two factors: 1) the effective dose of the ultimate
carcinogen in contact with cellular targets during a sensitive step of the cell cycle and 2) the time-persistence of a high steady state level of the
carcinogen.