Modulation of the covalent binding of aryl hydrocarbon metabolites to DNA in vitro after treatment of rats and mice with trans-stilbene oxide

Abstract

The effect of trans-stilbene oxide (TSO) induction on the microsome-catalyzed binding of polycyclic aromatic hydrocarbon metabolites to DNA was investigated using two rodent species (Sprague-Dawley rat and C57BL/6N or NMRI Swiss mouse) and 2 different binding substrates (benzo[a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene). It was determined that TSO exerts 2 separate effects on polycycik aromatic hydrocarbons — it increases the rate of oxidation at the K-region of the molecule due to its induction of specific monooxygenases, and it increases the rate of deactivation of epoxide intermediates by induction of microsomai epoxide hydrolase activity. The importance of these individual effects were determined by inducing monooxygenase activity with BP, altering regiospecificity and inducing epoxide hydrolase (EH) activity with TSO, assessing the combined inductive effects of TSO and BP, inhibiting EH with 1,1,1-trichloropropene oxide, or increasing its activity by the addition of pure enzyme. This study shows that these effects are similar for both substrates examined, and that the effect of TSO on the binding to DNA of highly carcinogenic bay-region diol-epoxides is multi-faceted, due to its multiple inductive effects.