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Research ArticleArticle

Effects of Coexpression of UGT1A9 on Enzymatic Activities of Human UGT1A Isoforms

Ryoichi Fujiwara, Miki Nakajima, Hiroyuki Yamanaka, Akiko Nakamura, Miki Katoh, Shin-ichi Ikushiro, Toshiyuki Sakaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition May 2007, 35 (5) 747-757; DOI: https://doi.org/10.1124/dmd.106.014191
Ryoichi Fujiwara
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Miki Nakajima
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Hiroyuki Yamanaka
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Akiko Nakamura
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Miki Katoh
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Shin-ichi Ikushiro
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Toshiyuki Sakaki
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Tsuyoshi Yokoi
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Abstract

We established stable HEK293 cell lines expressing double isoforms, UGT1A1 and UGT1A9, UGT1A4 and UGT1A9, or UGT1A6 and UGT1A9, as well as stable cell lines expressing each single isoform. To analyze the protein-protein interaction between the UGT1As, we investigated the thermal stability and resistance to detergent. UGT1A9 uniquely demonstrated thermal stability, which was enhanced in the presence of UDP-glucuronic acid (>90% of control), and resistance to detergent. Interestingly, UGT1A1, UGT1A4, and UGT1A6 acquired thermal stability and resistance to detergent by the coexpression of UGT1A9. An immunoprecipitation assay revealed that UGT1A6 and UGT1A9 interact in the double expression system. Using the single expression systems, it was confirmed that estradiol 3-O-glucuronide, imipramine N-glucuronide, serotonin O-glucuronide, and propofol O-glucuronide formations are specific for UGT1A1, UGT1A4, UGT1A6, and UGT1A9, respectively. By kinetic analyses, we found that the coexpressed UGT1A9 significantly affected the kinetics of estradiol 3-O-glucuronide formation (decreased Vmax), imipramine N-glucuronide formation (increased Km and Vmax), and serotonin O-glucuronide formation (decreased Vmax) catalyzed by UGT1A1, UGT1A4, and UGT1A6, respectively. On the other hand, the coexpressed UGT1A1 increased Km and decreased the Vmax of the propofol O-glucuronide formation catalyzed by UGT1A9. The coexpressed UGT1A4 and UGT1A6 also increased the Vmax of the propofol Oglucuronide formation by UGT1A9. This is the first study showing that human UGT1A isoforms interact with other isoforms to change the enzymatic characteristics.

Footnotes

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

  • doi:10.1124/dmd.106.014191.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; UDPGA, UDP-glucuronic acid; HPLC, high performance liquid chromatography; 4-MU, 4-methylumbelliferone; 7-HFC, 7-hydroxy-4-trifluoromethylcoumarin; PBS, phosphate-buffered saline; HPLC, high-performance liquid chromatography.

    • Received December 2, 2006.
    • Accepted February 7, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (5)
Drug Metabolism and Disposition
Vol. 35, Issue 5
1 May 2007
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Research ArticleArticle

Effects of Coexpression of UGT1A9 on Enzymatic Activities of Human UGT1A Isoforms

Ryoichi Fujiwara, Miki Nakajima, Hiroyuki Yamanaka, Akiko Nakamura, Miki Katoh, Shin-ichi Ikushiro, Toshiyuki Sakaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition May 1, 2007, 35 (5) 747-757; DOI: https://doi.org/10.1124/dmd.106.014191

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Research ArticleArticle

Effects of Coexpression of UGT1A9 on Enzymatic Activities of Human UGT1A Isoforms

Ryoichi Fujiwara, Miki Nakajima, Hiroyuki Yamanaka, Akiko Nakamura, Miki Katoh, Shin-ichi Ikushiro, Toshiyuki Sakaki and Tsuyoshi Yokoi
Drug Metabolism and Disposition May 1, 2007, 35 (5) 747-757; DOI: https://doi.org/10.1124/dmd.106.014191
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