Abstract
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 Vmax andKm values. UGT1A6 showed a more restricted acceptance of phenolic substrates compared with UGT1A9. However, the affinity of UGT1A6 for these compounds exhibited higherKm 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 theKm value to the generated descriptors correlated well with the experimental datar2 value of 0.996 for UGT1A6 andr2 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 Vmax decreased as the 4-substituent increased in size, and a trend was observed when UGT1A6 Vmax was plotted against molecular volume. The larger UGT1A6 substrates were typified by low activity and lower Km 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. TheKm values for UGT1A9 showed a similar relationship to UGT1A6 but with much lowerKm values and greater variability in range of this value.
Footnotes
- Abbreviations used are::
- UGT
- UDP-glucuronosyltransferases
- QSAR
- quantitative structure activity relationship
- WHIM
- weighted holistic invariant molecular
- MS-WHIM
- molecular surface-WHIM
- AT-WHIM
- atomic-WHIM
- UDPGA
- UDP-glucuronic acid
- HPLC
- high-performance liquid chromatography
- Received November 12, 2001.
- Accepted March 11, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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