In the present study it is demonstrated that MO-QSARs (quantitative structure activity relationships based on calculated molecular orbital substrate characteristics) of cytochrome P450-catalysed biotransformation of benzene derivatives obtained in previous studies for Wistar rats, can be extrapolated to other species, including man. First, it was demonstrated that the regioselectivity of the in vivo aromatic hydroxylation of two fluorobenzene derivatives can be quantitatively predicted, on the basis of the calculated density distribution of the reactive pi-electrons in the aromatic ring of the fluorobenzene derivative, for all experimental animal species tested. Second, it was investigated whether the preferential site for in vitro aromatic hydroxylation of 3-fluoroaniline could be predicted on the basis of the same calculated parameter, This was done because extrapolation to human systems requires in vitro instead of in vivo experiments. The results obtained indicated that the variation in the regioselectivity of the aromatic hydroxylation of 3-fluoroaniline by liver microsomes from different species, including man, was only a few percent, and was mainly directed by calculated chemical reactivity characteristics of the 3-fluoroaniline substrate. Finally, possibilities for the extrapolation from rat to other species, of the MO-QSAR for the rate of in vitro C4 hydroxylation of a series of aniline derivatives converted in an iodosobenzene-supported microsomal cytochrome P450 system, were investigated. Experiments with liver microsomes from rats, mice, rabbit and man resulted in clear MO-QSARs with correlation coefficients for the relationship between the In k(cat) and the E(HOMO) of the aniline substrates that were greater than or equal to 0.97 in all cases, Thus, the results of the present study clearly demonstrate that MO-QSARs previously described for Wistar rats can be extrapolated to mice, rabbit, guinea pig and even to man. Regioselectivities obtained and QSAR lines for the rate of conversion plotted against calculated E(HOMO) values of the aniline derivatives are similar for the various species investigated. Altogether, these results strongly support the conclusion that the conversion of the relatively small benzene derivatives in the relatively large and aspecific active sites of the mammalian cytochromes P450, even when derived from various species, are mainly dependent on chemical reactivity parameters of the substrates. Therefore, the results of the present study support the hypothesis that MO-based QSARs obtained in rat for the cytochrome P450 catalysed aromatic hydroxylation of benzene derivatives can provide a basis for prediction of biotransformation pathways in different species, including man.
