Diversifying selection detected in only a minority of xenobiotic-metabolizing <i>CYP1-3</i> genes among primate species

1. Primates exhibit a high degree of among-species dietary diversity, which likely exposes them to varying levels of xenobiotic compounds. Here, we examined the evolution of primate <i>CYP1-3</i> gene families, and we classified the 15 <i>CYP1-3</i> gene subfamilies as either xenobiotic-metabolizing (XM) or endogenous-metabolizing (EM) based on sources in the P450 literature. 2. We predicted that XM P450s would show (1) greater variability in gene-copy number and (2) more evidence of diversifying selection and, especially on codons that encode the substrate-recognition sites (SRSs) for the final enzymes. 3. Counter to our first prediction, EM and XM P450s showed similar levels of variation in gene-copy number. We did find, however, that four XM P450 subfamilies (<i>CYP2C, CYP2D, CYP2E,</i> and <i>CYP3A</i>) showed evidence of diversifying selection while no EM subfamilies demonstrated any consistent signal of diversifying selection. Of these four, <i>CYP2C, CYP2D,</i> and <i>CYP3A</i> showed significant links between SRSs and diversifying selection. 4. These results reveal an amount of evolutionary dynamism that would not be expected when viewing P450 subfamilies along a simple binary EM/XM spectrum. We recommend that comparative studies of cytochrome P450 evolution should focus on the <i>CYP2C, CYP2D, CYP2E,</i> and <i>CYP3A</i> subfamilies.