Endotoxin downregulates hepatic expression of P-glycoprotein and MRP2 in 2-acetylaminofluorene-treated rats.
In liver, the ATP-dependent transporters P-glycoprotein (PGP) and multidrug resistance protein-2 (MRP2) are involved in the secretion of numerous drugs and toxins in bile. Although constitutive levels of PGP and MRP-2 are decreased in rat liver after exposure to endotoxin, it is possible that induced forms of these transporters may be alternately affected. In vitro, the hepatocarcinogen, 2-acetylaminofluorene (AAF) induces expression of PGP and MRP2. Thus, we examined the influence of endotoxin on the expression of PGP and MRP2 in AAF-treated rats. Expression of PGP and MRP2 was analyzed on Westerns and by RT-PCR in livers obtained from endotoxin and control groups. In vivo, AAF treatment significantly induced PGP/mdr1 expression and imposed a significant reduction in the expression of spgp. MRP2 protein and mRNA levels were not altered by AAF administration. Endotoxin administration to both AAF-treated and non-AAF-treated rats elicited significant reductions in the protein and mRNA expression of MRP2 and PGP (P < 0.05). Our data indicate that endotoxin suppresses the overexpression of PGP and constitutive expression of MRP2 in AAF-treated rats. Furthermore, in vivo administration of AAF, which maximally induces PGP does not induce MRP2.
Tang
W
W
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S-2S2, Canada.
Yi
C
C
Kalitsky
J
J
Piquette-Miller
M
M
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001711:Biotransformation; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D004731:Endotoxins / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002273:Carcinogens; D002352:Carrier Proteins; D004731:Endotoxins; D012333:RNA, Messenger; D015073:2-Acetylaminofluorene