Abstract
Fenofibric acid (FA), the active moiety of fenofibrate, is an agonist of the peroxisome proliferator-activated nuclear receptor α that modulates triglyceride and cholesterol profiles. Lipid response to fenofibrate and FA serum concentrations is highly variable. Although FA is reported to be almost exclusively inactivated by UDP-glucuronosyltransferases (UGTs) into FA-glucuronide (FA-G), the contribution of UGT isoenzymes has never been systematically assessed. Heterologously expressed human UGT1A and UGT2B and their coding variants were tested for FA glucuronidation using liquid chromatography/mass spectrometry. Recombinant UGT2B7 presented the highest Vmax/Km value (2.10 μl/min/mg), 16-fold higher than the activity of other reactive UGTs, namely, UGT1A3, UGT1A6, and UGT1A9 (0.13, 0.09, and 0.02 μl/min/mg, respectively). UGT2B7.1 (His268) and UGT2B7.2 (Tyr268) enzyme activity was similar, whereas UGT1A3.2 (R11A47), UGT1A3.3 (Trp11), and UGT1A9.3 (Thr33) showed 61 to 96% reduced Vmax/Km values compared with the respective (1) reference proteins. FA-G formation by a human liver bank (n = 48) varied by 10-fold, but the rate of formation was not associated with common genetic variations in UGT1A3, UGT1A6, UGT1A9, and UGT2B7. Correlation with activities for the probe substrates zidovudine (UGT2B7; r2 = 0.75), mycophenolic acid (UGT1A9; r2 = 0.42), fulvestrant (UGT1A3; r2 = 0.36), but not serotonin (UGT1A6; r2 = 0.06) indicated a primary role for UGT2B7 and lesser roles of UGT1A9 and UGT1A3 in hepatic FA glucuronidation. This was confirmed by a strong correlation of FA-G formation with UGT2B7 protein content and inhibition by fluconazole, a known UGT2B7 selective inhibitor. Additional studies are required to identify genetic factors contributing to the observed FA glucuronidation variability.
- FA, fenofibric acid
- UGT, UDP-glucuronosyltransferase
- HLM, human liver microsome
- FA-G, fenofibric acid-glucuronide
- HPLC, high-performance liquid chromatography
- MS/MS, tandem mass spectrometry
- HEK, human embryonic kidney
- OHCE, hydroxy-catecholestrogen
- CV, coefficient of variation
- MPA, mycophenolic acid.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM-061834]; and the Canadian Institutes of Health Research [Grant MOP-42392]. J.T. was the recipient of a studentship award from the Fonds de la Recherche en Santé du Québec. M.-O.B.-B. was supported by a Canada Graduate Scholarship Doctoral Research Award from the Canadian Institutes for Health Research and by the Canadian Federation of University Women (CFUW) Dr. Marion Elder Grant Fellowship, funded by CFUW Wolfville.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029058
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J.T. and M.-O.B.-B. contributed equally to this work.
- Received June 17, 2009.
- Accepted July 29, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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