Genes Encoding Xenobiotic Detoxification Proteins evolve by gene death, duplication and positive selection

ABSTRACT There was a huge variability in the pharmacokinetics of drugs between species, which means in the way it will be transformed, degraded and eliminated, as well as the variation in drug absorption, plasma concentration over time, half-life, bioavailability, volume of distribution, metabolism rate, and routes of excretion. To understand the reasons of such a variability between species, we have studied here the evolution of genes encoding drug-metabolizing enzymes, i.e. the 9 key genes that are known to play a principal role in this process: UGT1A6, UGT1A, CYP2B, CYP2C, CYP2D, UGT2B, CYP3A, NAT1, GSTP1. We show here that a lot of these genes have been lost during evolution in several vertebrate species: UGT1A6 in gorilla, cat dog, ruminants, pig, UGT1A in artiodactyla, UGT2B in all vertebrate species except human and gorilla, CYP2C in all vertebrate species except primates and mouse. Several of these genes have duplicated such as UGT1A in human (4 copies), CYP3A in most of vertebrate species studied here except the cat, CYP2D in the mouse (9 copies). Furthermore, several of these genes undergone evolution by positive selection such as CYP2D6, UGT1A, CYP2C (particularly in squirrel), UGT1A. Overall, this study shows that the evolution by gene death, gene duplication, and positive selection is partly responsible for the great variability in the ability of vertebrate species to metabolize drugs.