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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

Felcy Pavithra Selwyn, Julia Yue Cui and Curtis D. Klaassen
Drug Metabolism and Disposition October 2015, 43 (10) 1572-1580; DOI: https://doi.org/10.1124/dmd.115.063545
Felcy Pavithra Selwyn
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
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Julia Yue Cui
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
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Curtis D. Klaassen
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
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Abstract

Intestinal bacteria have been shown to be important in regulating host intermediary metabolism and contributing to obesity. However, relatively less is known about the effect of intestinal bacteria on the expression of hepatic drug-processing genes in the host. This study characterizes the expression of hepatic drug-processing genes in germ-free (GF) mice using RNA-Seq. Total RNA were isolated from the livers of adult male conventional and GF C57BL/6J mice (n = 3 per group). In the livers of GF mice, the mRNA of the aryl hydrocarbon receptor target gene Cyp1a2 was increased 51%, and the mRNA of the peroxisome proliferator-activated receptor α (PPARα) target gene Cyp4a14 was increased 202%. Conversely, the mRNA of the constitutive androstane receptor (CAR) target gene Cyp2b10 was decreased 57%, and the mRNA of the pregnane X receptor target gene Cyp3a11 was decreased 87% in GF mice. Although other non-Cyp phase-1 enzymes in the livers of GF mice were only moderately affected, there was a marked down-regulation in the phase-2 enzymes glutathione S-transferases p1 and p2, as well as a marked up-regulation in the major bile acid transporters Na+-taurocholate cotransporting polypeptide and organic anion-transporting polypeptide 1b2, and the cholesterol transporter ATP-binding cassette transporter Abcg5/Abcg8. This study demonstrates that intestinal bacteria regulate the expression of a large number of drug-processing genes, which suggests that intestinal bacteria are responsible for some individual differences in drug responses.

Footnotes

    • Received January 27, 2015.
    • Accepted May 7, 2015.
  • This research was supported by the National Institutes of Health National Institute of Environmental Health Sciences and National Institute of General Medical Sciences [Grants ES019487 and GM111381].

  • Part of this work was presented as a thesis: Selwyn Samraj FP (2014), Alterations in bile acid homeostasis and drug metabolism in germ-free mice. Ph.D. thesis, University of Kansas, Lawrence. Part of this work was presented as a poster: Selwyn FP, Cui YJ, Klaassen CD (2014). “Expression of drug processing genes in livers of germ-free mice.” Society of Toxicology 53rd Annual Meeting; 2014 Mar 24–27; Phoenix, AZ. Society of Toxicology, Reston, VA.

  • dx.doi.org/10.1124/dmd.115.063545.

  • ↵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 (10)
Drug Metabolism and Disposition
Vol. 43, Issue 10
1 Oct 2015
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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

Drug Processing Genes in Germ-Free Mice

Felcy Pavithra Selwyn, Julia Yue Cui and Curtis D. Klaassen
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1572-1580; DOI: https://doi.org/10.1124/dmd.115.063545

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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

Drug Processing Genes in Germ-Free Mice

Felcy Pavithra Selwyn, Julia Yue Cui and Curtis D. Klaassen
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1572-1580; DOI: https://doi.org/10.1124/dmd.115.063545
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