Carcinogenesis, Vol 18, 1521-1527, Copyright © 1997 by Oxford University Press
Y Cai, H Kleiner, D Johnston, A Dubowski, S Bostic, W Ivie and J DiGiovanni
Several naturally occurring coumarins previously found to be potent
inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or
pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on
formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene
(DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin
tumor initiation by these polycyclic aromatic hydrocarbons (PAH).
Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min
prior to an initiating dose of B[a]P, significantly decreased total
covalent binding of B[a]P to DNA in a dose-dependent manner 24 h after
treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P
by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total
covalent binding of B[a]P by 59%. In addition, formation of the major
(+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both
of these coumarins. In contrast, bergamottin and coriandrin did not
significantly decrease covalent binding of DMBA to epidermal DNA at doses
of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are
more potent inhibitors of hepatic PROD activity, significantly reduced
overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when
applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA
adduct formation at similar doses but to a lesser extent. Imperatorin at a
dose of 400 nmol dramatically decreased formation of covalent DNA adducts
derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a
potent inhibitor of tumor initiation by B[a]P while coriandrin was less
effective in this regard. Imperatorin was an effective inhibitor of skin
tumor initiation by DMBA and also inhibited complete carcinogenesis by this
PAH. At dose levels higher than those effective against DMBA, imperatorin
also inhibited tumor initiation by B[a]P. The results demonstrate that
several naturally occurring coumarins possess the ability to block DNA
adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The
mechanism for reduced DNA adduct formation and tumor initiation appears to
involve inhibition of the P450s involved in the metabolic activation of
these hydrocarbons. Finally, the differential effects of certain coumarins
on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful
for dissecting the role of specific cytochromes P450 in their metabolic
activation.
ARTICLES
Effect of naturally occurring coumarins on the formation of epidermal DNA adducts and skin tumors induced by benzo[a]pyrene and 7,12- dimethylbenz[a]anthracene in SENCAR mice
University of Texas M.D. Anderson Cancer Center, Department of Carcinogenesis, Smithville 78957, USA.
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