title: Quantitative Atlas of Cytochrome P450, UDP-Glucuronosyltransferase, and Transporter Proteins in Jejunum of Morbidly Obese Subjects.
abstract: Protein expression levels of drug-metabolizing enzymes and transporters in human jejunal tissues excised from morbidly obese subjects during gastric bypass surgery were evaluated using quantitative targeted absolute proteomics. Protein expression levels of 15 cytochrome P450 (CYP) enzymes, 10 UDP-glucuronosyltransferase (UGT) enzymes, and NADPH-P450 reductase (P450R) in microsomal fractions from 28 subjects and 49 transporters in plasma membrane fractions from 24 of the same subjects were determined using liquid chromatography-tandem mass spectrometry. Based on average values, UGT1A1, UGT2B15, UGT2B17, SGLT1, and GLUT2 exhibited high expression levels (over 10 fmol/μg protein), though UGT2B15 expression was detected at a high level in only one subject. CYP2C9, CYP2D6, CYP3A5, UGT1A6, P450R, ABCG2, GLUT5, PEPT1, MCT1, 4F2 cell-surface antigen heavy chain (4F2hc), LAT2, OSTα, and OSTβ showed intermediate levels (1-10 fmol/μg protein), and CYP1A1, CYP1A2, CYP1B1, CYP2C18, CYP2C19, CYP2J2, CYP3A7, CYP4A11, CYP51A1, UGT1A3, UGT1A4, UGT1A8, UGT2B4, ABCC1, ABCC4, ABCC5, ABCC6, ABCG8, TAUT, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OCTN1, CNT2, PCFT, MCT4, GLUT4, and SLC22A18 showed low levels (less than 1 fmol/μg protein). The greatest interindividual difference (364-fold) was detected for UGT2B17. However, differences in expression levels of other quantified UGTs (except UGT2B15 and UGT2B17), CYPs (except CYP1A1 and CYP3A5), and P450R, and all quantified transporters, were within 10-fold. Expression levels of CYP1A2 and GLUT4 were significantly correlated with body-mass index. The levels of 4F2hc showed significant gender differences. Smokers showed increased levels of UGT1A1 and UGT1A3. These findings provide a basis for understanding the changes in molecular mechanisms of jejunal metabolism and transport, as well as their interindividual variability, in morbidly obese patients.
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Miyauchi
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes , Paris F-75010, France.|Pharmacokinetics and Pharmacochemistry Unit, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris , Paris F-75014, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Department of Surgery, Université Versailles Saint Quentin, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris , Boulogne 92100, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bouillot
authors.affiliation: Institut cardiométabolisme et nutrition (ICAN), Université Pierre et Marie Curie, Service de Nutrition, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris , Paris F-75013, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.affiliation: Institut cardiométabolisme et nutrition (ICAN), Université Pierre et Marie Curie, Service de Nutrition, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris , Paris F-75013, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Oppert
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes , Paris F-75010, France.|Department of Internal Medicine, Therapeutic Research Unit, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris , Paris F-75010, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouly
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes , Paris F-75010, France.|Department of Internal Medicine, Therapeutic Research Unit, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris , Paris F-75010, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bergmann
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes , Paris F-75010, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes , Paris F-75010, France.|Department of Internal Medicine, Therapeutic Research Unit, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris , Paris F-75010, France.
authors.forename: Célia
authors.initials: C
authors.lastname: Lloret-Linares
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051296:Glucose Transporter Type 5 / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009767:Obesity, Morbid / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism; D000074011:Peptide Transporter 1; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D027981:Symporters
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D051273:Glucose Transporter Type 2; D051296:Glucose Transporter Type 5; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D000074011:Peptide Transporter 1; C450859:SLCO2B1 protein, human; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human
keywords: BCRP/ABCG2; CYP; OATP2B1; UGT2B17; drug-metabolizing enzymes; morbid obesity; small intestine; transporter