Carcinogenesis, Vol 18, 215-222, Copyright © 1997 by Oxford University Press
Y Cai, W Baer-Dubowska, M Ashwood-Smith and J DiGiovanni
Several naturally occurring coumarins to which humans are routinely exposed
have been previously found to be potent inhibitors and inactivators of
cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic
microsomes and in a reconstituted system using purified human P450 1A1 [Cai
et al. (1993) Chem. Res. Toxicol., 6, 872- 879 and Cai et al. (1996) Chem.
Res. Toxicol., 9, 729-736]. In the present study, several of these
coumarins were investigated for their inhibitory effects on the metabolism
and metabolic activation of benzo[a]pyrene (B[a]P) and
7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes.
Initial analysis of B[a]P metabolism in cultured keratinocytes showed that
imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations
of 2 nM equal with B[a]P, reduced the formation of water-soluble
metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the
most potent inhibitors of the compounds examined. HPLC analysis of organic
solvent-soluble metabolites of B[a]P indicated that all the coumarins
tested significantly reduced the formation of individual B[a]P metabolites
(including phenols, diols and tetraols). However, the greatest effect was
on the formation of B[a]P tetraols. Additional experiments determined the
ability of selected coumarins to block covalent binding of B[a]P and DMBA
to DNA in keratinocytes. Bergamottin preferentially inhibited the binding
of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the
binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts
formed from B[a]P and DMBA indicated that both bergamottin and coriandrin
specifically inhibited the formation of anti diol-epoxide DNA adducts
derived from both hydrocarbons. The preferential inhibitory effect of
bergamottin and coriandrin on the formation of anti diol-epoxide adducts
derived from DMBA was further confirmed by separation of anti- and
syn-diol-epoxide- DNA adducts using immobilized boronate chromatography.
The current study demonstrates that certain naturally occurring coumarins
inhibited metabolic activation of B[a]P and DMBA in cultured mouse
keratinocytes and specifically inhibited the formation of DNA adducts
derived from the anti diol-epoxide diastereomers from either hydrocarbon.
The current data also suggest that certain naturally occurring coumarins
may possess anticarcinogenic activity toward polycyclic aromatic
hydrocarbons.
ARTICLES
Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured mouse keratinocytes
University of Texas MD Anderson Cancer Center, Department of Carcinogenesis, Smithville 78957, USA.
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