Thyroid hormone regulates the activity and expression  of the peptide transporter PEPT1 in Caco-2 cells

Ashida, Kayoko; Katsura, Toshiya; Motohashi, Hideyuki; Saya, Hideyuki; Inui, Ken Ichi

doi:10.1152/ajpgi.00344.2001

Cited by 57 publications

(37 citation statements)

References 34 publications

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“…The reason for the increased renal clearance of digoxin is considered to be a facilitation of tubular secretion (Bonelli et al, 1978); however, the mechanisms underlying the altered pharmacokinetics of digoxin in thyroid disease have not been fully elucidated. Previous studies have shown that thyroid hormone regulates the expression levels of various membrane transporters such as the fructose transporter GLUT5 (Matosin-Matekalo et al, 1999), the peptide transporter PEPT1 (Ashida et al, 2002), Na ϩ /K ϩ -ATPase (Giannella et al, 1993), and the Na ϩ /H ϩ exchanger NHE1 . Therefore, we hypothesized that the alteration in the plasma concentration of digoxin in patients with thyroid disorders might be due to changes in Pgp expression by thyroid hormone.…”

Section: Introductionmentioning

confidence: 99%

Modulation of P-Glycoprotein Expression in Hyperthyroid Rat Tissues

Nishio¹,

Katsura²,

Ashida³

et al. 2005

Drug Metab Dispos

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ABSTRACT:P-glycoprotein (Pgp) is expressed in various normal tissues and plays an important role in drug absorption and disposition. In addition, it is supposed that alterations in the expression levels of Pgp are involved in the inter-and intraindividual variability of pharmacokinetics of many drugs. Since pharmacokinetic properties of various drugs are altered in patients with thyroid disorders, we examined the expression of Pgp and mdr1a/1b mRNA in the kidney, liver, jejunum, and ileum from euthyroid and hyperthyroid rats. Western blot analysis revealed that Pgp expression was markedly increased in the kidney and liver of hyperthyroid rats. In contrast, it was slightly increased in the jejunum and ileum. mdr1a/1b mRNA levels were significantly increased in the kidney of hyperthyroid rats. However, they were not increased in the liver as well as in the jejunum and ileum of hyperthyroid rats. Expression levels of bile salt export pump and mdr2 mRNA were also unchanged in hyperthyroid rat liver. Taken together, these findings suggest that thyroid hormone induces Pgp expression in a tissue-selective manner, and that the modulation of mdr1a/1b mRNA expression in the hyperthyroid state varies among tissues.P-glycoprotein (Pgp) is expressed in various tissues such as brain, liver, kidney, and intestine (Cordon-Cardo et al., 1990;Brady et al., 2002) and plays an important role in defining the pharmacokinetics of many drugs. Pgp functions as a drug efflux pump and exports hydrophobic, bulky drugs such as anticancer agents, cardiac glycosides, ␤-blockers, calcium channel blockers, and immunosuppressants. Since Pgp has a broad substrate recognition, the concomitant administration of drugs often causes drug interactions by inhibiting Pgpmediated transport (Yu, 1999). For example, inhibition of digoxin transport in cultured epithelial cell lines expressing Pgp by various drugs such as quinidine (Tanigawara et al., 1992;Fromm et al., 1999), verapamil (Tanigawara et al., 1992, and cyclosporin A (Okamura et al., 1993) has been reported. We have also demonstrated that the renal clearance of digoxin was decreased in patients receiving a concomitant administration of clarithromycin and, accordingly, the plasma concentration of digoxin was increased (Wakasugi et al., 1998). The mechanism of this interaction was explained by the inhibition of Pgp-mediated tubular secretion of digoxin. On the other hand, recent studies have demonstrated that changes in the expression levels of Pgp affect the pharmacokinetic properties of Pgp substrates. Greiner et al. (1999) reported that rifampin administration induced Pgp expression in the small intestine and reduced the plasma concentration of orally administered digoxin, suggesting that alterations in the expression levels of Pgp are closely involved in the inter-and intraindividual variability of pharmacokinetics of Pgp substrates.Thyroid hormone is secreted from the thyroid gland to maintain normal growth and development, normal body temperature, and normal energy levels. Most of its effect...

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Section: Introductionmentioning

confidence: 99%

Modulation of P-Glycoprotein Expression in Hyperthyroid Rat Tissues

Nishio¹,

Katsura²,

Ashida³

et al. 2005

Drug Metab Dispos

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“…Furthermore, molecular identification of PEPT1 and PEPT2 provided a novel opportunity to determine the mechanisms of their regulation. For example, it was reported that the intestinal PEPT1 is regulated by various factors, including dietary conditions (Ogihara et al, 1999;Shiraga et al, 1999;Naruhashi et al, 2002), hormones such as insulin, leptin, and thyroid hormone (Buyse et al, 2001;Ashida et al, 2002;Gangopadhyay et al, 2002), epidermal growth factor (Nielsen et al, 2001), development (Shen et al, 2001), and some pharmacological agents (Fujita et al, 1999;Berlioz et al, 2000).…”

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confidence: 99%

Altered Diurnal Rhythm of Intestinal Peptide Transporter by Fasting and Its Effects on the Pharmacokinetics of Ceftibuten

Pan

Takato²,

Okuda³

et al. 2003

J Pharmacol Exp Ther

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We previously demonstrated that Hϩ /peptide cotransporter PEPT1 shows a diurnal rhythm in the rat small intestine. In the present study, we examined the effect of food intake on the diurnal rhythm of intestinal PEPT1 using fed and fasted rats and also determined whether such variation affected the pharmacokinetics of peptide-like drugs. In fed rats, PEPT1 protein level was significantly higher at 8:00 PM than at 8:00 AM. However, during fasting for 2 to 4 days, the differences of PEPT1 protein levels between 8:00 AM and 8:00 PM gradually disappeared. Intestinal absorption of an oral antibiotic ceftibuten (CETB), a pharmacological substrate for PEPT1, was also greater at 8:00 PM than at 8:00 AM in fed rats, but not different in 4-day fasted rats. In contrast to PEPT1 protein levels, PEPT1 mRNA levels retained a diurnal rhythm after 4 days of fasting. Pharmacokinetic analyses of CETB after intraintestinal administration demonstrated that both C max and area under the plasma concentration-time curve from 0 to 3 h were greater at 8:00 PM than at 8:00 AM in fed rats. In contrast, pharmacokinetic parameters showed no significant difference between 8:00 AM and 8:00 PM for intraintestinal administration in 4-day fasted rats and for intravenous administration in fed and 4-day fasted rats. These findings suggested that the diurnal rhythm of intestinal PEPT1 transport activity was disrupted by fasting and that diurnal variation of intestinal PEPT1 functionality could influence the pharmacokinetics of peptide-like drugs such as CETB.

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“…Moreover, although hyperplasia and increased uptake were evident even at 1 wk post-resection, cellular mRNA levels in the ileal enterocyte decreased 3-fold at 1 wk post-resection, while cellular protein levels remained unchanged. This decrease in gene expression of PepT1 despite the strong catabolic stress with a 70% proximal small bowel resection might be related to some counterregulatory hormones (such as epidermal growth factor and triiodothyronine) or other negative regulators of PepT1 gene expression as has been suggested by other in vitro studies (in cell cultures) [23][24]; however, we have no objective data to support this statement. Similar findings of a decrease in jejunal mRNA for PepT1 were reported after enterectomy in rabbits, but no protein or uptake studies were carried out [25].…”

Section: Discussionmentioning

confidence: 68%