Vol. 30, Issue 6, 734-738, June 2002

Quantitative Structure Activity Relationships for the Glucuronidation of Simple Phenols by Expressed Human UGT1A6 and UGT1A9

Brian T. Ethell, Sean Ekins, Jibo Wang, and Brian Burchell

Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, Dundee, United Kingdom (B.T.E., B.B.); and Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (S.E., J.W.)

UGT1A6 and UGT1A9 have both been demonstrated to rapidly glucuronidate simple phenolic compounds. A series of simple phenols were selected and screened with both isoforms and then used as model substrates for the generation of V_max and K_m values. UGT1A6 showed a more restricted acceptance of phenolic substrates compared with UGT1A9. However, the affinity of UGT1A6 for these compounds exhibited higher K_m values than UGT1A9, although rates of turnover were similar. Molecular surface-weighted holistic invariant molecular descriptors were generated for each substrate and used to produce the first quantitative structure activity relationship models generated for expressed human UGTs. Models relating log of the K_m value to the generated descriptors correlated well with the experimental data r² value of 0.996 for UGT1A6 and r² value of 0.83 for UGT1A9. Cross validation by a leave-one-out method also showed good predictive capability within the subset with a q² value of 0.98 for UGT1A6 and q² value of 0.73 for UGT1A9. Empirically, UGT1A6 V_max decreased as the 4-substituent increased in size, and a trend was observed when UGT1A6 V_max was plotted against molecular volume. The larger UGT1A6 substrates were typified by low activity and lower K_m values than their smaller counterparts. Extrapolating from this, it was demonstrated that phenols with large 4-substituents, which were not UGT1A6 substrates, could inhibit 4-ethylphenol glucuronidation. The K_m values for UGT1A9 showed a similar relationship to UGT1A6 but with much lower K_m values and greater variability in range of this value.