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.
Warrington
Jill S
JS
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Greenblatt
David J
DJ
von Moltke
Lisa L
LL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D015870:Gene Expression / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1