METABOLIC TRANSFORMATION OF HALOGENATED AND OTHER ALKENES - A THEORETICAL APPROACH - ESTIMATION OF METABOLIC REACTIVITIES FOR IN-VIVO CONDITIONS

Olefinic hydrocarbons are metabolized in vivo by cytochrome P450-dependent monooxygenases to the corresponding epoxides. The maximum in vivo metabolic rate, which is an important toxicokinetic parameter, has been used to define the apparent rate constant (k(app)) describing in vivo metabolic reactivity of alkenes. To derive k(app) the metabolic rate normalized per body weight was divided by the corresponding average alkene concentration in the body at saturation conditions of 90%. Toxicokinetic data obtained in rats for 13 compounds (ethene, 1-fluoroethene, 1,1-difluoroethene, 1-chloroethene, 1,1-dichloroethene, cis-1,2-dichloroethene, trans-1,2-dichloroethene, 1,1,2-trichloroethene, perchloroethene, propene, isoprene, 1,3-butadiene and styrene) have been used to calculate k(app) values. A theoretical model, based on the assumption that in vivo epoxidation can be described as a cytochrome P450-mediated electrophilic reaction, has been developed. Using the olefinic hydrocarbons as an example it has been shown that k(app) can be explained solely by the following molecular parameters: ionization potential, dipole moment and pi-electron density. These molecular parameters were calculated by a quantum chemical method or were taken from the literature. Furthermore, the model was tested also by predicting k(app) for isobutene, an alkene which was not used for the model development. The predicted value of k(app) agrees with the one derived experimentally, demonstrating that molecular parameters of halogenated and other alkenes can be used to predict in vivo metabolic reactivity. The model presented here is a first contribution to the ultimate goal to predict toxicokinetic parameters for in vivo conditions based on physicochemical parameters of enzymes and compounds exclusively.