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-depen dent monooxygenases to the corresponding epoxides. The maximum in vivo metabolic rate, which is an important toxicokinetic parameter, has be en used to define the apparent rate constant (k(app)) describing in vi vo metabolic reactivity of alkenes. To derive k(app) the metabolic rat e normalized per body weight was divided by the corresponding average alkene concentration in the body at saturation conditions of 90%. Toxi cokinetic data obtained in rats for 13 compounds (ethene, 1-fluoroethe ne, 1,1-difluoroethene, 1-chloroethene, 1,1-dichloroethene, cis-1,2-di chloroethene, trans-1,2-dichloroethene, 1,1,2-trichloroethene, perchlo roethene, propene, isoprene, 1,3-butadiene and styrene) have been used to calculate k(app) values. A theoretical model, based on the assumpt ion that in vivo epoxidation can be described as a cytochrome P450-med iated electrophilic reaction, has been developed. Using the olefinic h ydrocarbons as an example it has been shown that k(app) can be explain ed solely by the following molecular parameters: ionization potential, dipole moment and pi-electron density. These molecular parameters wer e calculated by a quantum chemical method or were taken from the liter ature. Furthermore, the model was tested also by predicting k(app) for isobutene, an alkene which was not used for the model development. Th e predicted value of k(app) agrees with the one derived experimentally , demonstrating that molecular parameters of halogenated and other alk enes can be used to predict in vivo metabolic reactivity. The model pr esented here is a first contribution to the ultimate goal to predict t oxicokinetic parameters for in vivo conditions based on physicochemica l parameters of enzymes and compounds exclusively.