Clinically Relevant Multidrug Transporters Are Regulated by

May 16, 2017 - For this purpose, tissue samples were collected from six intestinal sites obtained from six healthy tissue donors. The expression of 75...
2 downloads 11 Views 1MB Size
Subscriber access provided by Warwick University Library

Article

Clinically relevant multidrug transporters are regulated by microRNAs along the human intestine Henrike Bruckmueller, Paul Martin, Meike Kaehler, Sierk Haenisch, Marek Ostrowski, Marek Drozdzik, Werner Siegmund, Ingolf Cascorbi, and Stefan Oswald Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 16 May 2017 Downloaded from http://pubs.acs.org on May 17, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics

Clinically relevant multidrug transporters are regulated by microRNAs along the human intestine

Henrike Bruckmueller1, Paul Martin1, Meike Kähler1, Sierk Haenisch1, Marek Ostrowski2, Marek Drozdzik3, Werner Siegmund4, Ingolf Cascorbi1,*, Stefan Oswald4

1

Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-

Holstein, Campus Kiel;

2

Department of General and Transplantation Surgery,

Pomeranian Medical University, Szczecin, Poland, 3Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland, 4Center of Drug Absorption and Transport (C_DAT), Department of Clinical Pharmacology, University Medicine, Greifswald; Germany

Funding Sources: InnoProfile grant 03IPT613X (BMBF); National Science Centre, Cracow, Poland grant UMO-2015/17/B/NZ7/03066.

*Corresponding author: Ingolf Cascorbi, MD, PhD Institute of Experimental and Clinical Pharmacology University Hospital Schleswig-Holstein, Campus Kiel Arnold-Heller-Str. 3 24105 Kiel, Germany Phone: +49-431-500 30400 Fax: +49-431-500 30400 E-Mail: [email protected]

1

ACS Paragon Plus Environment

Molecular Pharmaceutics

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Graphic

2

ACS Paragon Plus Environment

Page 2 of 33

Page 3 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics

Abstract

Intestinal drug transporters are crucial determinants for absorption and oral bioavailability of drugs. In healthy tissue donators, a recent study revealed profound discrepancies between mRNA expression and protein abundance as well as differences in the protein content between small and large intestine for clinically relevant multidrug transporters as the ATP binding cassette transporter subfamily B member 1 (ABCB1) and subfamily C member 3 (ABCC3) and the solute carrier family 15 member 1 (SLC15A1, PEPT1). As the mechanisms underlying these observations remained unclear, the aim of the present study was to elucidate the intestinal regio-specific microRNA profile under physiological conditions and to identify specific microRNAs contributing to the posttranscriptional regulation of major drug transporters. For this purpose tissue samples were collected from six intestinal sites obtained from six healthy tissue donors. The expression of 754 microRNAs was determined using qRT-PCR based low density arrays and microRNA expression levels were correlated with transporter protein abundance quantified by targeted proteomics. A total of 241 microRNA-transporter pairs were identified, showing significant negative correlations to protein abundance (p