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First published on October 1, 2004; DOI: 10.1124/jpet.104.071290

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Received for publication May 12, 2004.
Revised September 21, 2004.
Accepted for publication September 30, 2004.

Upregulation of P-glycoprotein expression in small intestine under chronic serotonin-depleted conditions in rats

Hideo Hiraoka 1, Naoji Kimura 1, Yumiko Furukawa 1, Ken-ichi Ogawara 1, Toshikiro Kimura 1, Kazutaka Higaki 1*

1 Okayama University

* Address correspondence to: E-mail: higaki{at}pheasant.pharm.okayama-u.ac.jp

Abstract

To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HT-depleted rats prepared by intraperitoneal administration of p-chlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in-vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under 5-HT-depleted condition.


Key words: P-glycoprotein, brush border membrane, enteric nervous system, qunidine, serotonin, small intestine


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