Contribution of the UGT2 enzyme family to the metabolism of xenobiotics (2015)

Undergraduates: Matthew Fay, Trang Nguyen, Jay Snouwaert, and Beverly Koller

Faculty Advisor: Beverly Koller
Department: Chemistry

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Glucuronidation is an important defense mechanism against drugs, toxins, and endogenous wastes in humans. UDP-Glucuronosyltransferases (UGTs) conjugate a sugar acid, glucuronic acid, to a variety of lipophilic substrates, decreasing toxicity and increasing water solubility to facilitate excretion. Based on genetic phylogeny, UGTs are divided into the UGT1 and UGT2 families, each comprising several isoforms. Determining which isoforms target a compound in vivo is essential to understanding the compound¿¿¿s pharmacokinetics and toxicity, but this is complicated by the large number of UGTs and by the substrate promiscuity of many isoforms. To address this limitation, we have created a mutant mouse in which the entire Ugt2 family has been excised. Using this line, termed ¿¿Ugt2, we show that UGT2 enzymes are essential for metabolism of the NSAID Naproxen. In contrast, ¿¿Ugt2 animals show decreased excretion of the environmental pseudoestrogen bisphenol A (BPA), but glucuronidation still occurs. At least in mouse, clearance of BPA is jointly carried out by UGT1 and UGT2 enzymes, and the affinities for BPA of both families in vitro are similar. Our data suggest that human neonates, identified as highly vulnerable to BPA toxicity due to UGT2 deficiency until 7 months of age, may be protected by the UGT1 family, which is expressed rapidly after birth. These studies demonstrate the utility of this mouse line in determining the contribution of the UGT2 family to metabolism of xenobiotics.