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Research ArticleArticle

Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

Rika Hirashima, Hirofumi Michimae, Hiroaki Takemoto, Aya Sasaki, Yoshinori Kobayashi, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Molecular Pharmacology September 2016, 90 (3) 265-274; DOI: https://doi.org/10.1124/mol.116.104174
Rika Hirashima
Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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 (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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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Hiroaki Takemoto
Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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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Aya Sasaki
Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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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Yoshinori Kobayashi
Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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 (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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 (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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 (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, 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

Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3′,5′-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)—an enzyme involved in the metabolism of T4—by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile–treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels.

Footnotes

    • Received March 2, 2016.
    • Accepted July 11, 2016.
  • 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 and GM086713].

  • dx.doi.org/10.1124/mol.116.104174.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (3)
Molecular Pharmacology
Vol. 90, Issue 3
1 Sep 2016
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Research ArticleArticle

Induction of the UGT1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

Rika Hirashima, Hirofumi Michimae, Hiroaki Takemoto, Aya Sasaki, Yoshinori Kobayashi, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Molecular Pharmacology September 1, 2016, 90 (3) 265-274; DOI: https://doi.org/10.1124/mol.116.104174

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Research ArticleArticle

Induction of the UGT1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

Rika Hirashima, Hirofumi Michimae, Hiroaki Takemoto, Aya Sasaki, Yoshinori Kobayashi, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara
Molecular Pharmacology September 1, 2016, 90 (3) 265-274; DOI: https://doi.org/10.1124/mol.116.104174
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