RT Journal Article
SR Electronic
T1 The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 730
OP 736
DO 10.1124/jpet.103.061234
VO 309
IS 2
A1 Warrington, Jill S.
A1 Greenblatt, David J.
A1 von Moltke, Lisa L.
YR 2004
UL http://jpet.aspetjournals.org/content/309/2/730.abstract
AB We investigated the effect of age on P-glycoprotein (P-gp) expression and function in rat liver, intestine, kidney, and endothelial cells of the blood-brain barrier (BBB) and lymphocytes. Flow cytometric analysis was used to examine P-gp expression in lymphocytes from male Fischer-344 rats from three age groups (young at 3-4 months, intermediate at 13-14 months, and old at 25-26 months). In addition, P-gp function in lymphocytes was assessed by measuring the ability of the P-gp inhibitor verapamil to limit the efflux of the fluorescent P-gp substrate rhodamine 123. P-gp expression was evaluated in the remaining four tissues by Western blot analysis. The effect of age on P-gp expression was tissue-specific. Although lymphocytic and hepatic P-gp expression increased with age, renal P-gp content was lower in the old kidneys. No statistical difference was observed in P-gp expression in intestinal microsomes or in BBB cell lysates among the three age groups. P-gp function was also increased by 6- to 8-fold in lymphocytes from the old rats. When P-gp expression was compared with CYP3A expression in these rats (reported elsewhere in this journal), we found that P-gp expression increased with age, whereas CYP3A expression and activity declined in the old livers. The converse pattern was observed in the kidney. Thus, age-related changes in P-gp expression and function are likely to be tissue-specific, and these changes may be inversely related to differences in CYP3A expression. The American Society for Pharmacology and Experimental Therapeutics