Upregulation in the expression of multidrug resistance protein Mrp1 mRNA and protein by increased bilirubin production in rat.
Earlier studies suggest that Mrp1 may mediate ATP-dependent cellular extrusion of unconjugated bilirubin (UCB). We studied the serial responses of expression of Mrp1 mRNA and protein in rats with increased bilirubin production due to hemolysis induced by phenylhydrazine (PHZ) treatment. Mrp1 mRNA was analyzed by quantitative PCR and protein by Western blot. Hepatic expression of Mrp1 mRNA and protein peaked at day 3 of PHZ treatment. Splenic expression of Mrp1 mRNA peaked within 24h and returned to baseline at day 5 whereas Mrp1 protein expression peaked at day 3. Pretreatment with heme-oxygenase inhibitor, tin mesoporphyrin, blunted the increase in serum UCB and erased the overexpression of Mrp1 both in liver and spleen. Thus, the upregulation of Mrp1 in hemolysis is mediated by UCB and/or other products of heme oxygenase, further supporting a role of Mrp1 in UCB transport and protection from its cellular toxicity.
Cekic
Dean
D
Centro Studi Fegato, AREA Science Park and Department BBCM, University of Trieste, Trieste, Italy.
Bellarosa
Cristina
C
Garcia-Mediavilla
Maria Victoria
MV
Rigato
Igino
I
Pascolo
Lorella
L
Ostrow
J Donald
JD
Tiribelli
Claudio
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009928:Organ Specificity; D010659:Phenylhydrazines / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008665:Metalloporphyrins; D010659:Phenylhydrazines; D011524:Protoporphyrins; D012333:RNA, Messenger; C030299:phenylhydrazine; C032628:tin protoporphyrin IX; D001663:Bilirubin