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: Yun-Yun Shao, Jing Huang, Yan-Rong Ma, Miao Han, Kang Ma, Hong-Yan Qin, Zhi Rao, Xin-An Wu
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 93 Issue 8 Pg. 633-9 (Aug 2015) ISSN: 1205-7541 [Electronic] Canada
• PMID: 26053941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Constitutive Androstane Receptor
• Receptors, Cytoplasmic and Nuclear
• Serotonin
• Trinitrobenzenesulfonic Acid
• 5-Hydroxytryptophan
• Fenclonine

Topics

• 5-Hydroxytryptophan (administration & dosage)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Colon (drug effects, metabolism)
• Constitutive Androstane Receptor
• Disease Models, Animal
• Enterochromaffin Cells (drug effects, metabolism)
• Fenclonine (administration & dosage)
• Irritable Bowel Syndrome (blood, chemically induced, physiopathology)
• Liver (drug effects, metabolism)
• Male
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Serotonin (blood)
• Signal Transduction
• Trinitrobenzenesulfonic Acid