EVOLUTION OF THE CYTOCHROME-P450 SUPERFAMILY - SEQUENCE ALIGNMENTS AND PHARMACOGENETICS

The evolution of the cytochrome P450 (CYP) superfamily is described, w ith particular reference to major events in the development of biologi cal forms during geological time. It is noted that the currently accep ted timescale for the elaboration of the P450 phylogenetic tree exhibi ts close parallels with the evolution of terrestrial biota. Indeed, th e present human P450 complement of xenobiotic-metabolizing enzymes may have originated from coevolutionary 'warfare' between plants and anim als during the Devonian period about 400 million years ago. A number o f key correspondences between the evolution of P450 system and the cou rse of biological development over time, point to a mechanistic molecu lar biology of evolution which is consistent with a steady increase in atmospheric oxygenation beginning over 2000 million years ago, wherea s dietary changes during more recent geological time may provide one p ossible explanation for certain species differences in metabolism. Ali gnment between P450 protein sequences within the same family or subfam ily, together with across-family comparisons, aid the rationalization of drug metabolism specificities for different P450 isoforms, and can assist in an understanding of genetic polymorphisms in P450-mediated o xidations at the molecular level. Moreover, the variation in P450 regu latory mechanisms and inducibilities between different mammalian speci es are likely to have important implications for current procedures of chemical safety evaluation, which rely on pure genetic strains of lab oratory bred rodents for the testing of compounds destined for human e xposure. (C) 1998 Elsevier Science B.V. All rights reserved.