EFFECT OF NATURALLY-OCCURRING COUMARINS ON THE FORMATION OF EPIDERMALDNA-ADDUCTS AND SKIN TUMORS INDUCED BY BENZO[A]PYRENE AND 7,12-DIMETHYLBENZ[A]ANTHRACENE IN SENCAR MICE

Several naturally occurring coumarins previously found to be potent in hibitors of mouse hepatic ethoxyresorufin-O-deethylase (PROD) and/or p entoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracen e (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 mi n 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 re duced total covalent binding of B[a]P by 59%, In addition, formation o f the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins, In contrast, bergamottin and coria ndrin did not significantly decrease covalent binding of DMBA to epide rmal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isop impinellin, 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 c oumarins also inhibited B[a]P-DNA adduct formation at similar doses bu t to a lesser extent, Imperatorin at a dose of 400 nmol dramatically d ecreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA, Bergamottin was a potent inhibitor of t umor initiation by B[a]P while coriandrin was less effective in this r egard, Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH, At do se levels higher than those effective against DMBA, imperatorin also i nhibited tumor initiation by B[a]P, The results demonstrate that sever al naturally occurring coumarins possess the ability to block DNA addu ct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appear s to involve inhibition of the P450s involved in the metabolic activat ion of these hydrocarbons, Finally, the differential effects of certai n 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.