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.