The effect of age on P-glycoprotein expression and function in the Fischer-344 rat.

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.