COMPARATIVE MO-QSAR STUDIES IN VARIOUS SPECIES INCLUDING MAN

In the present study it is demonstrated that MO-QSARs (quantitative st ructure activity relationships based on calculated molecular orbital s ubstrate characteristics) of cytochrome P450-catalysed biotransformati on of benzene derivatives obtained in previous studies for Wistar rats , can be extrapolated to other species, including man. First, it was d emonstrated that the regioselectivity of the in vivo aromatic hydroxyl ation 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 w hether the preferential site for in vitro aromatic hydroxylation of 3- fluoroaniline could be predicted on the basis of the same calculated p arameter, This was done because extrapolation to human systems require s in vitro instead of in vivo experiments. The results obtained indica ted that the variation in the regioselectivity of the aromatic hydroxy lation of 3-fluoroaniline by liver microsomes from different species, including man, was only a few percent, and was mainly directed by calc ulated chemical reactivity characteristics of the 3-fluoroaniline subs trate. 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 wit h liver microsomes from rats, mice, rabbit and man resulted in clear M O-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 Wista r rats can be extrapolated to mice, rabbit, guinea pig and even to man . Regioselectivities obtained and QSAR lines for the rate of conversio n plotted against calculated E(HOMO) values of the aniline derivatives are similar for the various species investigated. Altogether, these r esults strongly support the conclusion that the conversion of the rela tively small benzene derivatives in the relatively large and aspecific active sites of the mammalian cytochromes P450, even when derived fro m various species, are mainly dependent on chemical reactivity paramet ers of the substrates. Therefore, the results of the present study sup port the hypothesis that MO-based QSARs obtained in rat for the cytoch rome P450 catalysed aromatic hydroxylation of benzene derivatives can provide a basis for prediction of biotransformation pathways in differ ent species, including man.