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Ontogeny of P-Glycoprotein in Mouse Intestine, Liver, and Kidney
  1. Burhan Mahmood,
  2. Monica J. Daood,
  3. Claudia Hart,
  4. Thor W.R. Hansen,
  5. Jon F. Watchko
  1. From the Department of Pediatrics (B.M., M.J.D., C.H., J.F.W.), Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pa, Norway
  2. Department of Pediatrics (T.W.H.), Rikshopitalet, University of Oslo, Norway.
  1. Address correspondence to: J.F. Watchko, MD, Department of Pediatrics, Magee-Womens Hospital, 300 Halket Street, Pittsburgh, PA 15213. E-mail jwatchko{at}mail.magee.edu
  2. This work was supported by grants HD-35847 and NS-38993 from the National Institutes of Health, the Irene McClenahan Young Investigator Research Fund of the Magee-Womens Health Research Foundation, the Mario Lemieux Centers for Patient Care and Research, and the 25 Club of Magee-Womens Hospital.

Abstract

Background P-glycoprotein (Pgp) is an ATP-dependent, integral plasma-membrane efflux pump that is constitutively expressed on (i) adult apical brush-border epithelial cells of the intestine, (ii) the bile canalicular face of hepatocytes, and (iii) the brush border epithelium of renal proximal tubules. This Pgp tissue distribution and localization affects the absorption, distribution, metabolism, and excretion of Pgp substrates. Little is known regarding the ontogeny of Pgp expression in these tissues.

Methods Postnatal expression of Pgp on brush border membranes of small intestine, liver, and kidney as a function of maturity from birth through adulthood was determined using Western immunoblotting and immunohistochemical techniques. Tissue was isolated from FVB mice at four different ages: day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adult (Ad). The relative expression of Pgp protein on Western immunoblots was assessed by scanning densitometry and indexed as a percentage (mean±SEM) of the adult levels.

Results On Western immunoblots, Pgp expression was limited at birth (19±6% of Ad) and increased significantly with maturation in intestine (ANOVA, P <0.005). In contrast, hepatic (113±12% of Ad) and renal (96±15% of Ad) Pgp expression were at adult levels at birth. The tissue-specific developmental pattern of Pgp expression was confirmed by immunohistochemistry.

Conclusions We conclude that Pgp is expressed in a tissue-specific and developmentally regulated fashion and speculate that developmental modulation of intestine-Pgp expression may affect the oral bioavailability of Pgp substrates.

Keywords
  • Development
  • pharmacology
  • drug transporters

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