Abstract
[Purpose] UDP-glucuronosyltransferases (UGT) are pivotal xenobiotic-conjugating enzymes for drugs, environmental pollutants and dietary compounds such as polyphenols. UGT isoforms of mammal are encoded in several gene family and show various substrate specificity and regio-specificity towards structurally different compounds. In this study, orthologus enzymes of mammalian UGT1A1 and 1A6 were functionally analyzed in comparison with those of human.
[Methods] Mammalian UGT1A1 and 1A6 (human, cynomolgus monkey, marmoset, rat, and mouse) were expressed in budding yeast cells, Saccharomyces cerevisiae AH22, using a multicopy plasmid (pGYR). Microsomal fractions were prepared from each transformat of yeast cells. Protein expression of UGT1A was confirmed by Western blot analysis.
[Results and Discussion] In the identity of amino acid sequence, UGT1A1 and 1A6 show 93-95% of identity in each isoform of primates or rodents. All UGT1A1 isoform have a glucuronidating activity toward bilirubin as degradation product from heme. UGT1A1 and 1A6 showed the ability of glucuronidation towards several substrates such as scopoletin, bisphenol A, and 1-hydroxypyrene with isoform- and species-dependent difference of activity. In addition, several polyphenols as dietary functional compounds were regio-specific glucuronidated by UGT1A1 and 1A6. These results indicated that some differences in enzyme properties of UGT1A1 and 1A6 need to be considered when extrapolating the glucuronidation of xenobiotics in model animals to human.
