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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients

Hideto Jinno, Mayumi Saeki, Yoshiro Saito, Toshiko Tanaka-Kagawa, Nobumitsu Hanioka, Kimie Sai, Nahoko Kaniwa, Masanori Ando, Kuniaki Shirao, Hironobu Minami, Atsushi Ohtsu, Teruhiko Yoshida, Nagahiro Saijo, Shogo Ozawa and Jun-ichi Sawada
Journal of Pharmacology and Experimental Therapeutics August 2003, 306 (2) 688-693; DOI: https://doi.org/10.1124/jpet.103.051250
Hideto Jinno
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Mayumi Saeki
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Yoshiro Saito
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Toshiko Tanaka-Kagawa
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Nobumitsu Hanioka
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Kimie Sai
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Nahoko Kaniwa
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Masanori Ando
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Kuniaki Shirao
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Hironobu Minami
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Atsushi Ohtsu
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Teruhiko Yoshida
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Nagahiro Saijo
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Shogo Ozawa
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Jun-ichi Sawada
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Abstract

SN-38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of the antitumor prodrug irinotecan, is conjugated and detoxified to SN-38 10-O-β-d-glucuronide by hepatic UDP-glucuronosyltransferase (UGT) 1A1. Recent studies have revealed that other UGT1A isoforms, UGT1A7 and UGT1A9, also participate in SN-38 glucuronidation. Although several genetic polymorphisms are reported for UGT1A1 and UGT1A7 that affect the SN-38 glucuronidation activities, no such polymorphisms have been identified for UGT1A9. In the present study, UGT1A9 exon 1 and its flanking regions were sequenced from 61 Japanese cancer patients who were all treated with irinotecan. A novel nonsynonymous single nucleotide polymorphism was identified in UGT1A9 exon 1, heterozygous 766G>A resulting in the amino acid substitution of D256N. The wild-type and D256N UGT1A9s were transiently expressed at similar protein levels in COS-1 cells, and their membrane fractions were characterized in vitro for the glucuronidation activities toward SN-38. The apparent Km values were 19.3 and 44.4 μM, and the Vmax values were 2.94 and 0.24 pmol/min/mg of membrane protein for the wild-type and D256N variant, respectively. The SN-38 glucuronidation efficiency (normalized Vmax/Km) of D256N was less than 5% that of wild-type UGT1A9. These results clearly indicate that the D256N variant is essentially nonfunctional with regard to SN-38 glucuronidation. These findings highlight the importance of further studies into the potential influence of UGT1A9 D256N variant to irinotecan metabolism in vivo.

Footnotes

  • This study was supported in part by the Program for Promotion of Fundamental Studies in Health Sciences (MPJ-1 and MPJ-6) of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan.

  • Hideto Jinno and Mayumi Saeki contributed equally to this article.

  • DOI: 10.1124/jpet.103.051250.

  • ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; UGT, UDP-glucuronosyltransferase; SN-38G, 7-ethyl-10-hydroxycamptothecin 10-O-β-d-glucuronide; PCR, polymerase chain reaction.

    • Received March 6, 2003.
    • Accepted April 21, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 2
1 Aug 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients

Hideto Jinno, Mayumi Saeki, Yoshiro Saito, Toshiko Tanaka-Kagawa, Nobumitsu Hanioka, Kimie Sai, Nahoko Kaniwa, Masanori Ando, Kuniaki Shirao, Hironobu Minami, Atsushi Ohtsu, Teruhiko Yoshida, Nagahiro Saijo, Shogo Ozawa and Jun-ichi Sawada
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 688-693; DOI: https://doi.org/10.1124/jpet.103.051250

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients

Hideto Jinno, Mayumi Saeki, Yoshiro Saito, Toshiko Tanaka-Kagawa, Nobumitsu Hanioka, Kimie Sai, Nahoko Kaniwa, Masanori Ando, Kuniaki Shirao, Hironobu Minami, Atsushi Ohtsu, Teruhiko Yoshida, Nagahiro Saijo, Shogo Ozawa and Jun-ichi Sawada
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 688-693; DOI: https://doi.org/10.1124/jpet.103.051250
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