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Research ArticleArticle

Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain

Yuki Kutsuno, Rika Hirashima, Masaya Sakamoto, Hiroko Ushikubo, Hirofumi Michimae, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Drug Metabolism and Disposition July 2015, 43 (7) 1071-1076; DOI: https://doi.org/10.1124/dmd.115.063719
Yuki Kutsuno
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Rika Hirashima
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Masaya Sakamoto
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Hiroko Ushikubo
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Hirofumi Michimae
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Tomoo Itoh
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Robert H. Tukey
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Ryoichi Fujiwara
Department of Pharmaceutics (Y.K., R.H., M.S., T.I., R.F.), Department of Molecular Pharmacology (H.U.), and Division of Biostatistics (H.M.), School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.)
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Abstract

Although UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, they are also involved in the metabolism of endogenous compounds. Certain substrates of UGTs, such as serotonin and estradiol, play important roles in the brain. However, the expression of UGTs in the human brain has not been fully clarified. Recently, humanized UGT1 mice (hUGT1 mice) in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus have been developed. In the present study, the expression pattern of UGT1As in brains from humans and hUGT1 mice was examined. We found that UGT1A1, 1A3, 1A6, and 1A10 were expressed in human brains. The expression pattern of UGT1As in hUGT1 mouse brains was similar to that in human brains. In addition, we examined the expression of UGT1A1 and 1A6 in the cerebellum, olfactory bulbs, midbrain, hippocampus, and cerebral cortex of hUGT1 mice. UGT1A1 in all brain regions and UGT1A6 in the cerebellum and cerebral cortex of 6-month-old hUGT1 mice were expressed at a significantly higher rate than those of 2-week-old hUGT1 mice. A difference in expression levels between brain regions was also observed. Brain microsomes exhibited glucuronidation activities toward estradiol and serotonin, with mean values of 0.13 and 5.17 pmol/min/mg, respectively. In conclusion, UGT1A1 and UGT1A6 might play an important role in function regulation of endogenous compounds in a region- and age-dependent manner. Humanized UGT1 mice might be useful to study the importance of brain UGTs in vivo.

Footnotes

    • Received February 5, 2015.
    • Accepted May 7, 2015.
  • This work was supported by a Grant-in-Aid for Encouragement of Young Scientists B to R.F. [Grant 26870562]. This work was also supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P42-ES010337] and National Institute of General Medical Sciences [Grant R01-GM100481].

  • dx.doi.org/10.1124/dmd.115.063719.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Expression of Brain UGT1A1 and UGT1A6 in hUGT1 Mice

Yuki Kutsuno, Rika Hirashima, Masaya Sakamoto, Hiroko Ushikubo, Hirofumi Michimae, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1071-1076; DOI: https://doi.org/10.1124/dmd.115.063719

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Research ArticleArticle

Expression of Brain UGT1A1 and UGT1A6 in hUGT1 Mice

Yuki Kutsuno, Rika Hirashima, Masaya Sakamoto, Hiroko Ushikubo, Hirofumi Michimae, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1071-1076; DOI: https://doi.org/10.1124/dmd.115.063719
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