title: Serum serotonin reduced the expression of hepatic transporter Mrp2 and P-gp via regulating nuclear receptor CAR in PI-IBS rats.
abstract: Hepatic transporters and drug metabolizing enzymes (DMEs) play important roles in the pharmacological effects and (or) side-effects of many drugs, and are regulated by several mediators, including neurotransmitters. This work aimed to investigate whether serum levels of 5-hydroxytryptamine (5-HT) affected the expression of hepatic transporters or DMEs. The expression of hepatic transporters was assessed using the Western-blot technique in a 2,4,6-trinitrobenzenesulfonic-acid-induced rat model of post-infectious irritable bowel syndrome (PI-IBS), in which serum levels of 5-HT were significantly elevated. To further clarify the underlying mechanism, the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the 5-HT depleting agent parachlorophenylalanine (pCPA) were applied to adjust serum levels of 5-HT. Serum levels of 5-HT were measured using LC-MS/MS; the expression of hepatic transporters, DMEs, and nuclear receptors were examined by Western-blot technique. Our results showed that in PI-IBS rats the expression of multidrug resistance protein 2 (Mrp2) was significantly decreased, while colonic enterochromaffin cell density and serum levels of 5-HT were all significantly increased. Moreover, 5-HTP treatment significantly increased serum levels of 5-HT and decreased the expression of Mrp2 and glycoprotein P (P-gp), whereas treatment with pCPA markedly decreased serum levels of 5-HT and increased the expression of Mrp2 and P-gp. Our results indicated that serum 5-HT regulates the expression of Mrp2 and P-gp, and the underlying mechanism may be related to the altered expression of the nuclear receptor constitutive androstane receptor (CAR).
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.|b School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Shao
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.|b School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.|b School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Ma
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.|b School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Han
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.|b School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Ma
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Rao
authors.affiliation: a Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Xin-An
authors.initials: XA
authors.lastname: Wu
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D010134:Fenclonine / Q000008:administration & dosage; D043183:Irritable Bowel Syndrome / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012701:Serotonin / Q000097:blood*; D015398:Signal Transduction; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D012701:Serotonin; D014302:Trinitrobenzenesulfonic Acid; D006916:5-Hydroxytryptophan; D010134:Fenclonine
keywords: 5-HT; 5-HTP; enzymes métaboliques; foie; hepatic transporters; liver; metabolic enzymes; transporteurs hépatiques