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

• Published in: Drug metabolism and disposition Vol. 30; no. 6; pp. 734 - 738
• Main Authors: ETHELL, Brian T, EKINS, Sean, JIBO WANG, BURCHELL, Brian
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.06.2002
• Subjects: Biological and medical sciences; Cell Line; General pharmacology; Glucuronides - metabolism; Glucuronosyltransferase - metabolism; Humans; Isoenzymes - metabolism; Kinetics; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phenols - chemistry; Phenols - metabolism; Phenols - pharmacokinetics; Physicochemical properties. Structure-activity relationships; Quantitative Structure-Activity Relationship; Human; Substrate; Structure activity relation; UDP-glucuronosyltransferase; Enzyme; Isozyme; Transferases; Glycosyltransferases; Phenols; Glucuronic acid conjugation; Hexosyltransferases; Quantitative analysis
• DOI: 10.1124/dmd.30.6.734
• ISSN: 0090-9556

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 r 2 value of 0.996 for UGT1A6 and r 2 value of 0.83 for UGT1A9. Cross validation by a leave-one-out method also showed good predictive capability within the subset with a q 2 value of 0.98 for UGT1A6 and q 2 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.