Molecular cloning of the baboon UDP-glucuronosyltransferase 1A gene family: evolution of the primate UGT1 locus and relevance for models of human drug metabolism.

BACKGROUND

Glucuronidation by the UDP glucuronosyltransferase 1A enzymes (UGT1As) is a major pathway for elimination of drugs and endogenous substances, such as bilirubin.

OBJECTIVE

To identify the baboon UGT1A gene family, compare it with that of the human, and evaluate the baboon as a model for human glucuronidation.

METHODS AND RESULTS

Aligning the human and baboon UGT1 loci identified rearrangements occurring since the divergence of baboons and humans. The baboon UGT1A cDNAs were cloned and shown to have an orthologous relationship with several genes in the human UGT1A family. This indicates that most protein encoding UGT1A first exons were duplicated before the divergence of baboons and humans. Gene conversions interfered with the phylogenetic signal for exons 1A4, 1A5, and 1A10, and led to concerted evolution of exon groups 1A2-1A5 and 1A7-1A13. The activity of the baboon UGT1As resembled those of their human counterparts in glucuronidating endobiotics, such as serotonin, bilirubin, and various xenobiotics.

CONCLUSION

These insights demonstrate that the baboon has significant clinical relevance as a model for examining toxicological metabolism in humans.