Decreased expression and activity of P-glycoprotein in rat liver during acute inflammation.
OBJECTIVE
Drug disposition is often altered in inflammatory disease. Although the influence of inflammation on hepatic drug metabolism and protein binding has been well studied, its impact on drug transport has largely been overlooked. The multidrug resistance (MDR) gene product, P-glycoprotein (P-gp) is involved in the active secretion of a large variety of drugs. Our goal was to ascertain the influence of acute inflammation (AI) on the expression and functional activity of P-gp.


METHODS
AI was induced in rats through turpentine or lipopolysaccharide (LPS) administration. Expression of P-gp in liver was detected at the level of protein on Western blots using the monoclonal antibody C-219 and at the level of mRNA using an RNase protection assay. P-gp mediated transport activity was assessed by measuring the verapamil-inhibitable efflux of rhodamine 123 (R123) in freshly isolated hepatocytes.


RESULTS
Turpentine-induced AI significantly decreased the hepatic protein expression of P-gp isoforms by 50-70% and caused a significant 45-65% reduction in the P-gp mediated efflux of R123. Diminished mRNA levels of all three MDR isoforms were seen. LPS-induced AI similarly resulted in significantly reduced levels and activity of P-gp in liver. Although differences in the constitutive levels of P-gp were seen between male and female rats, the influence of AI on P-gp expression and activity was not gender specific.


CONCLUSIONS
Experimentally-induced inflammation decreases the in vivo expression and activity of P-gp in liver. This is the first evidence that expression of P-gp is modulated in response to experimentally-induced inflammation.
Piquette-Miller
M
M
Faculty of Pharmacy, University of Toronto, Ontario, Canada. m.piquette.miller@utoronto.ca
Pak
A
A
Kim
H
H
Anari
R
R
Shahzamani
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000208:Acute Disease; D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D012235:Rhodamines
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012235:Rhodamines; D020112:Rhodamine 123