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Mol Pharm. 2016 Aug 1;13(8):2691-701. doi: 10.1021/acs.molpharmaceut.6b00259. Epub 2016 Jul 20.

Effect of Intestinal Flora on Protein Expression of Drug-Metabolizing Enzymes and Transporters in the Liver and Kidney of Germ-Free and Antibiotics-Treated Mice.

Kuno T1,2, Hirayama-Kurogi M1,3,4, Ito S1,3,4, Ohtsuki S1,3,4.

Author information

1
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
2
Department of Drug Metabolism and Pharmacokinetics, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd. , 463-10 Kagasuno, Kawauchi-cho, Tokushima, Tokushima 771-0192, Japan.
3
Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
4
AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.

Abstract

Dysbiosis (alteration of intestinal flora) is associated with various host physiologies, including diseases. The purpose of this study was to clarify the effect of dysbiosis on protein expression levels in mouse liver and kidney by quantitative proteomic analysis, focusing in particular on drug-metabolizing enzymes and transporters in order to investigate the potential impact of dysbiosis on drug pharmacokinetics. Germ-free (GF) mice and antibiotics-treated mice were used as dysbiosis models. Expression levels of 825 and 357 proteins were significantly changed in the liver and kidney, respectively, of GF mice (vs specific-pathogen-free mice), while 306 and 178 proteins, respectively, were changed in antibiotics-treated mice (vs vehicle controls). Among them, 52 and 16 drug-metabolizing enzyme and transporter proteins were significantly changed in the liver and kidney, respectively, of GF mice, while 25 and 8, respectively were changed in antibiotics-treated mice. Expression of mitochondrial proteins was also changed in the liver and kidney of both model mice. In GF mice, Oatp1a1 was decreased in both the liver and kidney, while Sult1a1 and two Cyp enzymes were increased and Gstp1, four Cyp enzymes, three Ces enzymes, Bcrp1, and Oct1 were decreased in the liver. In antibiotics-treated mice, Cyp51a1 was increased and three Cyp enzymes, Bcrp1, and Bsep were decreased in the liver. Notably, the expression of Cyp2b10 and Cyp3a11 was greatly decreased in the liver of both models. Cyp2b activity in the liver microsomal fraction was also decreased. Our results indicate that dysbiosis changes the protein expression of multiple drug-metabolizing enzymes and transporters in the liver and kidney and may alter pharmacokinetics in the host.

KEYWORDS:

antibiotics; drug-metabolizing enzyme; intestinal flora; quantitative proteomics; targeted proteomics; transporter

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