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Research ArticleArticle

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Yukiko Sakakibara, Miki Katoh, Yuya Kondo and Masayuki Nadai
Drug Metabolism and Disposition March 2016, 44 (3) 370-377; DOI: https://doi.org/10.1124/dmd.115.067439
Yukiko Sakakibara
Pharmaceutics, Faculty of Pharmacy, Meijo University; 150 Yagotoyama, Tenpaku-ku, Nagoya 468–8503, Japan
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Miki Katoh
Pharmaceutics, Faculty of Pharmacy, Meijo University; 150 Yagotoyama, Tenpaku-ku, Nagoya 468–8503, Japan
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Yuya Kondo
Pharmaceutics, Faculty of Pharmacy, Meijo University; 150 Yagotoyama, Tenpaku-ku, Nagoya 468–8503, Japan
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Masayuki Nadai
Pharmaceutics, Faculty of Pharmacy, Meijo University; 150 Yagotoyama, Tenpaku-ku, Nagoya 468–8503, Japan
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This article has a correction. Please see:

  • Correction to “Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain” - April 01, 2016

Abstract

UDP-glucuronosyltransferase (UGT), a phase II drug-metabolizing enzyme, is expressed in the brain and can catalyze glucuronidation of endogenous and exogenous substrates in the brain. Thus, changes in UGT1A expression could affect homeostasis and drug efficacy. Phenobarbital (PB), a typical inducer of drug-metabolizing enzymes, has been reported to induce oxidative stress and epigenetic changes, which could alter UGT expression in the brain. Here, we aimed to clarify the effects of PB on Ugt1a6 and Ugt1a7 gene expression in rat brains. Sprague-Dawley rats were treated intraperitoneally with PB (80 mg/kg), once daily for 7 days. Ugt1a6 and Ugt1a7 mRNA expression levels were increased in the striatum and thalamus (Ugt1a6, 3.0- and 2.9-fold, respectively; Ugt1a7, 2.6- and 2.6-fold, respectively). Acetaminophen glucuronidation was also increased in the medulla oblongata and thalamus by 1.8- and 1.2-fold, respectively. The induction rates within different brain regions were correlated with Ugt1a6 and Ugt1a7 mRNA expression, and the degree of induction also correlated with that of NF-E2–related factor-2 mRNA. Measurement of oxidative stress markers suggested that PB induced oxidative stress in brain regions in which Ugt1a6 and Ugt1a7 mRNAs were increased. Moreover, histone modifications were altered by PB treatment, resulting in increased histone H3 lysine 4 trimethylation in the striatum and thalamus and decreased histone H3 lysine 9 trimethylation in the thalamus. These results suggested that oxidative stress and histone modifications may promote transcriptional activation of Ugt1a6 and Ugt1a7 genes. In summary, Ugt1a6 and Ugt1a7 mRNA levels were increased by PB treatment, which may alter pharmacokinetics in the brain.

Footnotes

    • Received September 25, 2015.
    • Accepted December 11, 2015.
  • This work was supported in part by JSPS KAKENHI [Grant No. 25460200] and the Hori Sciences and Arts Foundation.

  • dx.doi.org/10.1124/dmd.115.067439.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Phenobarbital Alters Brain UGT in Rats

Yukiko Sakakibara, Miki Katoh, Yuya Kondo and Masayuki Nadai
Drug Metabolism and Disposition March 1, 2016, 44 (3) 370-377; DOI: https://doi.org/10.1124/dmd.115.067439

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Research ArticleArticle

Phenobarbital Alters Brain UGT in Rats

Yukiko Sakakibara, Miki Katoh, Yuya Kondo and Masayuki Nadai
Drug Metabolism and Disposition March 1, 2016, 44 (3) 370-377; DOI: https://doi.org/10.1124/dmd.115.067439
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