Ontogeny of P-glycoprotein in mouse intestine, liver, and kidney

Background: P-glycoprotein (Pgp) is an ATP-dependent, integral plasma-membr ane efflux pump that is constitutively expressed on (i) adult apical brush- herder epithelial cells of the intestine, iii) the bile canalicular face of hepatocytes, and (iii) the brush border epithelium of renal proximal tubul es, This Pgp tissue distribution and localization affects the absorption, d istribution, metabolism, and excretion of Pgp substrates, Little is known r egarding the ontogeny of Pgp expression in these tissues. Methods: Postnatal expression of Pgp on brush border membranes of small int estine, Liver, and kidney as a function of maturity from birth through adul thood was determined using Western immunoblotting and immunohistochemical t echniques. 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 s canning 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 developm ental pattern of Pgp expression was confirmed by immunohistochemistry, Conclusions: We conclude that Pgp is expressed in a tissue-specific and dev elopmentally regulated fashion and speculate that developmental modulation of intestine-Pgp expression may affect the oral bioavailability of Pgp subs trates.