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 the 5-HT-depleted condition.
Footnotes
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This work was supported in part by a grant-in-aid for Scientific Research (C) from the Ministry of Education, Science, and Culture of Japan.
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doi:10.1124/jpet.104.071290.
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ABBREVIATIONS: P-gp, P-glycoprotein; MDR, multidrug resistance; ENS, enteric nervous system; NANC, nonadrenergic noncholinergic; 5-HT, serotonin, 5-hydroxytryptamine; PCPA, dl-p-chlorophenylalanine; PD, potential difference; Rm, tissue electrical resistance; HPLC, high-performance liquid chromatography; BBMV, brush-border membrane vesicle(s); MES, 4-morpholineethanesulfonic acid; PKC, protein kinase C.
- Received May 11, 2004.
- Accepted September 30, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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