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The authors discovered that the recombinant UGT1A6 enzyme preparation used in this work also contained UGT1A9. Accordingly, experiments involving UGT1A6 were repeated with HEK293 cell lysate expressing only this enzyme. Data reported for all other isoforms are accurate. The corrected version of the paper, which is in departure from print, follows.
Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, Australia (V.U., P.I.M., X.-H.G., D.G.-S., J.O.M.); and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (A.G., J.B.H.)
The glucuronidation kinetics of the prototypic substrates 4-methylumbelliferone (4MU) and 1-naphthol (1NP) by human UDP-glucuronosyltransferases (UGT) 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17 were investigated. Where activity was demonstrated, inhibitory effects of diclofenac, probenecid, and the solvents acetone, acetonitrile, dimethyl sulfoxide, ethanol, and methanol were characterized. All isoforms except UGT1A4 glucuronidated 4MU, whereas all but UGT 1A4, 2B15, and 2B17 metabolized 1NP. However, kinetic models varied with substrate (for the same isoform) and from isoform to isoform (with the same substrate). Hyperbolic (Michaelis-Menten), substrate inhibition, and sigmoidal kinetics were variably observed for both 4MU and 1NP glucuronidation by the various UGTs. Km or S50 (sigmoidal kinetics) and Vmax values varied 525- (8–4204 µM) and 5535-fold, respectively, for 4MU glucuronidation, and 1360- (1.3–1768 µM) and 560-fold, respectively, for 1NP glucuronidation. The use of a two-site model proved useful for those reactions exhibiting non-Michaelis-Menten glucuronidation kinetics. The organic solvents generally had a relatively minor effect on UGT isoform activity. UGT 1A6, 2B15, and 2B17 were most susceptible to the presence of solvent, although solvent-selective inhibition was occasionally observed with other isoforms. Diclofenac and probenecid inhibited all isoforms, precluding the use of these compounds for the reaction phenotyping of xenobiotic glucuronidation pathways in human tissues. Diclofenac and probenecid Ki values, determined for selected isoforms, ranged from 11 to 60 µM and 96 to 2790 µM, respectively. Overall, the results emphasize the need for the careful design and interpretation of kinetic and inhibition studies with human UGTs.
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