Can the chemical reactivity of an ultimate carcinogen be related to its carcinogenicity? An application to propylene oxide

In this article we report calculations of the activation free energy for a chemical reaction between propylene oxide and DNA, in particular with the guanine at the N7 position. Calculations were performed using Hartree-Fock and MP2 methods in conjunction with flexible basis sets. The effects of solvation were considered using the Langevin dipoles and solvent reaction field methods. The calculated activation free energies are in good agreement with the experimental value of 25.36 kcal/mol. Moreover, the reactivities of a series of ultimate carcinogens of the epoxy type toward DNA are shown to be related to their carcinogenicities. Higher reactivity is generally associated with higher carcinogenicity, although transport properties, reactions with ultimate carcinogen scavengers, and the DNA correction mechanism are also very important. It is very likely that the window of reactivity rather than a high reactivity value is the relevant measure of carcinogenicity, since highly reactive ultimate carcinogens interact with water and proteins before they reach DNA.