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Research ArticleArticle

Quantitative Characterization of Major Hepatic UDP-Glucuronosyltransferase Enzymes in Human Liver Microsomes: Comparison of Two Proteomic Methods and Correlation with Catalytic Activity

Brahim Achour, Alyssa Dantonio, Mark Niosi, Jonathan J. Novak, John K. Fallon, Jill Barber, Philip C. Smith, Amin Rostami-Hodjegan and Theunis C. Goosen
Drug Metabolism and Disposition October 2017, 45 (10) 1102-1112; DOI: https://doi.org/10.1124/dmd.117.076703
Brahim Achour
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Alyssa Dantonio
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Mark Niosi
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Jonathan J. Novak
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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John K. Fallon
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Jill Barber
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Philip C. Smith
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Amin Rostami-Hodjegan
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Theunis C. Goosen
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom (B.A., J.B., A.R.-H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut (A.D., M.N., J.J.N., T.C.G.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.)
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Abstract

Quantitative characterization of UDP-glucuronosyltransferase (UGT) enzymes is valuable in glucuronidation reaction phenotyping, predicting metabolic clearance and drug-drug interactions using extrapolation exercises based on pharmacokinetic modeling. Different quantitative proteomic workflows have been employed to quantify UGT enzymes in various systems, with reports indicating large variability in expression, which cannot be explained by interindividual variability alone. To evaluate the effect of methodological differences on end-point UGT abundance quantification, eight UGT enzymes were quantified in 24 matched liver microsomal samples by two laboratories using stable isotope-labeled (SIL) peptides or quantitative concatemer (QconCAT) standard, and measurements were assessed against catalytic activity in seven enzymes (n = 59). There was little agreement between individual abundance levels reported by the two methods; only UGT1A1 showed strong correlation [Spearman rank order correlation (Rs) = 0.73, P < 0.0001; R2 = 0.30; n = 24]. SIL-based abundance measurements correlated well with enzyme activities, with correlations ranging from moderate for UGTs 1A6, 1A9, and 2B15 (Rs = 0.52–0.59, P < 0.0001; R2 = 0.34–0.58; n = 59) to strong correlations for UGTs 1A1, 1A3, 1A4, and 2B7 (Rs = 0.79–0.90, P < 0.0001; R2 = 0.69–0.79). QconCAT-based data revealed generally poor correlation with activity, whereas moderate correlations were shown for UGTs 1A1, 1A3, and 2B7. Spurious abundance-activity correlations were identified in the cases of UGT1A4/2B4 and UGT2B7/2B15, which could be explained by correlations of protein expression between these enzymes. Consistent correlation of UGT abundance with catalytic activity, demonstrated by the SIL-based dataset, suggests that quantitative proteomic data should be validated against catalytic activity whenever possible. In addition, metabolic reaction phenotyping exercises should consider spurious abundance-activity correlations to avoid misleading conclusions.

Footnotes

    • Received May 10, 2017.
    • Accepted July 31, 2017.
  • https://doi.org/10.1124/dmd.117.076703.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (10)
Drug Metabolism and Disposition
Vol. 45, Issue 10
1 Oct 2017
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Research ArticleArticle

Quantitative Proteomics and Catalytic Activity of UGTs

Brahim Achour, Alyssa Dantonio, Mark Niosi, Jonathan J. Novak, John K. Fallon, Jill Barber, Philip C. Smith, Amin Rostami-Hodjegan and Theunis C. Goosen
Drug Metabolism and Disposition October 1, 2017, 45 (10) 1102-1112; DOI: https://doi.org/10.1124/dmd.117.076703

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Research ArticleArticle

Quantitative Proteomics and Catalytic Activity of UGTs

Brahim Achour, Alyssa Dantonio, Mark Niosi, Jonathan J. Novak, John K. Fallon, Jill Barber, Philip C. Smith, Amin Rostami-Hodjegan and Theunis C. Goosen
Drug Metabolism and Disposition October 1, 2017, 45 (10) 1102-1112; DOI: https://doi.org/10.1124/dmd.117.076703
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