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Research ArticleArticle

THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER

Hugo Girard, Lyne Villeneuve, Michael H. Court, Louis-Charles Fortier, Patrick Caron, Qin Hao, Lisa L. von Moltke, David J. Greenblatt and Chantal Guillemette
Drug Metabolism and Disposition July 2006, 34 (7) 1220-1228; DOI: https://doi.org/10.1124/dmd.106.009787
Hugo Girard
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Lyne Villeneuve
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Michael H. Court
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Louis-Charles Fortier
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Patrick Caron
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Qin Hao
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Lisa L. von Moltke
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David J. Greenblatt
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Chantal Guillemette
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Abstract

Polymorphisms in UGT1A9 were associated with reduced toxicity and increased response to irinotecan in cancer patients. UDP-glucuronosyltransferase (UGT) protein expression, glucuronidation activities for 7-ethyl-10-hydroxycamptothecin (SN-38), and probe substrates of the UGT1A9 and UGT1A1 were measured in 48 human livers to clarify the role of UGT1A9 variants on the in vitro glucuronidation of SN-38. Genotypes were assessed for UGT1A9 (–2152C>T, –275T>A, and –118T9>10), three novel UGT1A9 variants (–5366G>T, –4549T>C, and I399C>T), and UGT1A1 (–53TA6>7, –3156G>A, and –3279T>G). Of all the variants, the UGT1A9 I399C>T was associated with the most dramatic change in SN-38-glucuronide (SN-38G) (2.64-fold; p = 0.0007). Compared with UGT1A9 I399C/C, homozygous I399T/T presented elevated UGT1A1 and UGT1A9 proteins and higher glucuronidation of UGT1A9 and UGT1A1 substrates (p < 0.05). The very low linkage disequilibrium (r2 < 0.19) between UGT1A9 I399 and all the other UGT1A1 and UGT1A9 variants suggests a direct effect or linkage to unknown functional variant(s) relevant to SN-38 glucuronidation. The UGT1A9 –118T9/10 was also linked to alteration of SN-38 glucuronidation profiles in the liver (p < 0.05) and was associated with higher UGT1A1 protein (p = 0.03). However, UGT1A9 –118T10 appears to have low functional impact as a result of the lack of correlation with UGT1A9 protein levels and a modest 1.4-fold higher reporter gene expression associated with the –118T10 allele in HepG2 cells (p = 0.004). In contrast, the UGT1A9 –5366T, –4549C, –2152T, and –275A, associated with higher UGT1A9 protein (2-fold; p < 0.05), have no influence on SN-38G. Despite limitations resulting from sample size, results indicate that UGT1A9 I399 and –118T9/10 may represent additional candidates in combination with UGT1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research (CIHR; MOP-42392) and Canada Research Chair Program (C.G.), and by Grants GM-61834, GM-74369, DA-05258, MH-58435, DA-13209, DK-58496, DA-13834, AG-17880, and RR-00054 from the National Institutes of Health (M.H.C, D.J.G., L.L.v.M.).

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

  • doi:10.1124/dmd.106.009787.

  • ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; UGT, UDP-glucuronosyltransferase; SN-38G, SN-38-glucuronide; PCR, polymerase chain reaction; HPLC, high-performance liquid chromatography; LD, linkage disequilibrium; MPA, mycophenolic acid.

    • Received February 18, 2006.
    • Accepted March 29, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (7)
Drug Metabolism and Disposition
Vol. 34, Issue 7
1 Jul 2006
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Research ArticleArticle

THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER

Hugo Girard, Lyne Villeneuve, Michael H. Court, Louis-Charles Fortier, Patrick Caron, Qin Hao, Lisa L. von Moltke, David J. Greenblatt and Chantal Guillemette
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1220-1228; DOI: https://doi.org/10.1124/dmd.106.009787

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Research ArticleArticle

THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER

Hugo Girard, Lyne Villeneuve, Michael H. Court, Louis-Charles Fortier, Patrick Caron, Qin Hao, Lisa L. von Moltke, David J. Greenblatt and Chantal Guillemette
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1220-1228; DOI: https://doi.org/10.1124/dmd.106.009787
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