CYP3A metabolizes 50% of currently prescribed drugs and is frequently involved in clinically relevant drug interactions. The understanding of roles and regulations of the individual CYP3A genes in pharmacology and physiology is incomplete.
Using genomic sequences from 16 species we investigated the evolution of CYP3 genomic loci over a period of 450 million years.
CYP3A genes in amniota evolved from two ancestral CYP3A genes. Upon the emergence of eutherian mammals, one of them was lost, whereas, the other acquired a novel genomic environment owing to translocation. In primates, CYP3A underwent rapid evolutionary changes involving multiple gene duplications, deletions, pseudogenizations, and gene conversions. The expansion of CYP3A in catarrhines (Old World monkeys, great apes, and humans) differed substantially from New World primates (e.g. common marmoset) and strepsirrhines (e.g. galago). We detected two recent episodes of particularly strong positive selection acting on primate CYP3A protein-coding sequence: (i) on CYP3A7 early in hominoid evolution, which was accompanied by a restriction of its hepatic expression to fetal period and (ii) on human CYP3A4 following the split of the chimpanzee and human lineages. In agreement with these findings, three out of four positively selected amino acids investigated in previous biochemical studies of CYP3A affect the activity and regioselectivity.
CYP3A7 and CYP3A4 may have acquired catalytic functions especially important for the evolution of hominoids and humans, respectively.
aDepartment of Pharmacology, Johannes Gutenberg University Mainz
bInstitute of Anthropology, Johannes Gutenberg University Mainz, Mainz
cGenome Analysis, Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena
dInstitute of Experimental Pathology (ZMBE), University of Muenster, Muenster Germany
eWuhan Botanic Garden, Chinese Academy of Sciences, Wuhan, China
fDepartment of Genetics and Microbiology, University of Bari, Bari, Italy
Correspondence to Professor Dr Med. Leszek Wojnowski, Department of Pharmacology, Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany
Tel: +49 6131 3933460 or 37170; fax: +49 1803 5518 36727;
Received 15 June 2007 Accepted 8 October 2007