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Research ArticleArticle

Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid

Olivier Bernard, Jelena Tojcic, Kim Journault, Louis Perusse and Chantal Guillemette
Drug Metabolism and Disposition September 2006, 34 (9) 1539-1545; DOI: https://doi.org/10.1124/dmd.106.010553
Olivier Bernard
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Jelena Tojcic
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Kim Journault
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Louis Perusse
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Chantal Guillemette
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Abstract

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a standard immunosuppressive drug approved for clinical use in the prevention of acute allograft rejection after organ transplantation. This study examines the role of the genetic variants of UDP-glucuronosyltransferase (UGT) 1A8 and 2B7 enzymes involved in the formation of the primary metabolite of MPA, the inactive phenolic glucuronide (MPAG), and the reactive acyl glucuronide (AcMPAG). The first exon of UGT1A8 was first resequenced in the region encoding for the substrate binding domain in 254 Caucasians and 41 African Americans. Eight nonsynonymous changes were observed and led to the following amino acid substitutions: S43L, H53N, S126G, A144V, A173G, A231T, T240A, and C277Y. Thirteen haplotypes were inferred, comprising only two previously described alleles, namely, UGT1A8*2 (A173G) and UGT1A8*3 (C277Y). Upon stable expression in human embryonic kidney 293 cells, the UGT1A8*3 (C277Y), *5 (G173A240), *7 (A231T), *8 (S43L), and *9 (N53G) proteins were associated with the most profound decreases in the formation of MPAG and AcMPAG, indicating that these amino acids are critical for substrate binding and enzyme function. Altogether, the low-activity UGT1A8 enzymes are carried by 2.8 to 4.8% of the population. The variant of the UGT2B7 protein (UGT2B7*2 Y268), the main enzyme involved in the formation of AcMPAG, demonstrated a catalytic efficiency comparable with that of UGT2B7*1 (H268). In conclusion, although the common UGT2B7*2 variant is predicted to have limited impact, several UGT1A8 variants identified may potentially account for the large interindividual variance in MMF pharmacokinetics and deserve further clinical investigations.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research (MOP-42392) and Canada Research Chair Program (C.G.). O.B. is the recipient of a studentship award from the Fonds de la Recherche en Santé du Québec. C.G. is the chairholder of the Canada Research Chair in Pharmacogenomics.

  • Part of this work has been presented at the 13th North American Meeting of the International Society for the Study of Xenobiotics, 2005 October 23–27th, Maui, HI.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010553.

  • ABBREVIATIONS: MMF, mycophenolate mofetil; MPA, mycophenolic acid; IMPDH, inosine monosphospate dehydrogenase; UGT, UDP-glucuronosyltransferase; MPAG, mycophenolic acid phenolic glucuronide; AcMPAG, mycophenolic acid acyl glucuronide; SNP, single-nucleotide polymorphism; PCR, polymerase chain reaction; HEK, human embryonic kidney; CLint, intrinsic clearance.

    • Received April 19, 2006.
    • Accepted June 20, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid

Olivier Bernard, Jelena Tojcic, Kim Journault, Louis Perusse and Chantal Guillemette
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1539-1545; DOI: https://doi.org/10.1124/dmd.106.010553

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Research ArticleArticle

Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid

Olivier Bernard, Jelena Tojcic, Kim Journault, Louis Perusse and Chantal Guillemette
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1539-1545; DOI: https://doi.org/10.1124/dmd.106.010553
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