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OtherShort Communication

Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese

Yoshiro Saito, Kimie Sai, Keiko Maekawa, Nahoko Kaniwa, Kuniaki Shirao, Tetsuya Hamaguchi, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Yasuhide Yamada, Tomohide Tamura, Teruhiko Yoshida, Hironobu Minami, Atsushi Ohtsu, Yasuhiro Matsumura, Nagahiro Saijo and Jun-ichi Sawada
Drug Metabolism and Disposition February 2009, 37 (2) 272-276; DOI: https://doi.org/10.1124/dmd.108.024208
Yoshiro Saito
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Kimie Sai
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Keiko Maekawa
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Nahoko Kaniwa
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Kuniaki Shirao
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Tetsuya Hamaguchi
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Noboru Yamamoto
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Hideo Kunitoh
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Yuichiro Ohe
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Yasuhide Yamada
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Tomohide Tamura
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Teruhiko Yoshida
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Hironobu Minami
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Atsushi Ohtsu
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Yasuhiro Matsumura
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Nagahiro Saijo
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Jun-ichi Sawada
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Abstract

The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C>T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus, we evaluated the role of I399C>T in SN-38 glucuronidation using 177 Japanese cancer patients administered irinotecan. I399C>T was detected at a 0.636 allele frequency. This polymorphism was in strong linkage disequilibrium (LD) with UGT1A9*1b (–126_–118T9>T10, |D′| = 0.99) and UGT1A1*6 (211G>A, 0.86), in moderate LD with UGT1A1*60 (–3279T>G, 0.55), but weakly associated with UGT1A1*28 (–54_–39A(TA)6TAA>A(TA)7TAA, 0.25). Haplotype analysis showed that 98% of the I399C alleles were linked with low-activity haplotypes, either UGT1A1*6, *28, or *60. On the other hand, 85% of the T alleles were linked with the UGT1A1 wild-type haplotype *1. Although I399T-dependent increases in SN-38 glucuronide/SN-38 area under concentration-time curve (AUC) ratio (an in vivo marker for UGT1A activity) and decreases in SN-38 AUC/dose were apparent (P < 0.0001), these effects were no longer observed after stratified patients by UGT1A1*6, *28, or *60 haplotype. Thus, at least in Japanese populations, influence of I399C>T on SN-38 glucuronidation is attributable to its close association with either UGT1A1*6, *28, or *60.

Footnotes

  • This study was supported in part by the program for the Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation [Grant 05-25]; and a Health and Labour Sciences Research grant from the Ministry of Health, Labour and Welfare in Japan [Grant KHB1008].

  • Y.S. and K.S. contributed equally to this work.

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

  • doi:10.1124/dmd.108.024208.

  • ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; UGT, UDP-glucuronosyltransferase; SNP, single nucleotide polymorphism; SN-38G, SN-38 glucuronide; AUC, area under concentration-time curve; I399, UGT1A9 IVS1+399; LD, linkage disequilibrium.

  • ↵1 Current affiliation: Department of Medical Oncology, Oita University Faculty of Medicine, Yufu, Japan.

  • ↵2 Current affiliation: Medical Oncology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Kobe, Japan.

    • Received August 26, 2008.
    • Accepted October 30, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (2)
Drug Metabolism and Disposition
Vol. 37, Issue 2
1 Feb 2009
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Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese
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Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese

Yoshiro Saito, Kimie Sai, Keiko Maekawa, Nahoko Kaniwa, Kuniaki Shirao, Tetsuya Hamaguchi, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Yasuhide Yamada, Tomohide Tamura, Teruhiko Yoshida, Hironobu Minami, Atsushi Ohtsu, Yasuhiro Matsumura, Nagahiro Saijo and Jun-ichi Sawada
Drug Metabolism and Disposition February 1, 2009, 37 (2) 272-276; DOI: https://doi.org/10.1124/dmd.108.024208

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OtherShort Communication

Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese

Yoshiro Saito, Kimie Sai, Keiko Maekawa, Nahoko Kaniwa, Kuniaki Shirao, Tetsuya Hamaguchi, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Yasuhide Yamada, Tomohide Tamura, Teruhiko Yoshida, Hironobu Minami, Atsushi Ohtsu, Yasuhiro Matsumura, Nagahiro Saijo and Jun-ichi Sawada
Drug Metabolism and Disposition February 1, 2009, 37 (2) 272-276; DOI: https://doi.org/10.1124/dmd.108.024208
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