Kuno Takuya, Hirayama-Kurogi Mio, Ito Shingo, Ohtsuki Sumio
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
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.
Mol Pharm. 2016 Aug 1;13(8):2691-701. doi: 10.1021/acs.molpharmaceut.6b00259. Epub 2016 Jul 20.
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.
肠道菌群失调（肠道菌群的改变）与包括疾病在内的多种宿主生理状况相关。本研究的目的是通过定量蛋白质组学分析阐明肠道菌群失调对小鼠肝脏和肾脏中蛋白质表达水平的影响，特别关注药物代谢酶和转运蛋白，以研究肠道菌群失调对药物药代动力学的潜在影响。无菌（GF）小鼠和抗生素处理的小鼠被用作肠道菌群失调模型。与无特定病原体小鼠相比，GF小鼠肝脏和肾脏中分别有825种和357种蛋白质的表达水平显著变化，而抗生素处理的小鼠（与载体对照相比）肝脏和肾脏中分别有306种和178种蛋白质发生变化。其中，GF小鼠肝脏和肾脏中分别有52种和16种药物代谢酶和转运蛋白显著变化，而抗生素处理的小鼠肝脏和肾脏中分别有25种和8种发生变化。两种模型小鼠的肝脏和肾脏中线粒体蛋白的表达也发生了变化。在GF小鼠中，肝脏和肾脏中的Oatp1a1均降低，而肝脏中Sult1a1和两种Cyp酶增加，Gstp1、四种Cyp酶、三种Ces酶、Bcrp1和Oct1降低。在抗生素处理的小鼠中，肝脏中Cyp51a1增加，三种Cyp酶、Bcrp1和Bsep降低。值得注意的是，两种模型小鼠肝脏中Cyp2b10和Cyp3a11的表达均大幅降低。肝脏微粒体部分的Cyp2b活性也降低。我们的结果表明，肠道菌群失调会改变肝脏和肾脏中多种药物代谢酶和转运蛋白的蛋白质表达，并可能改变宿主的药代动力学。
