title: Hepatic P-glycoprotein changes with total parenteral nutrition administration.
abstract: BACKGROUND
  The mechanism(s) responsible for the development of parenteral nutrition-associated liver disease (PNALD) is unknown. Recently, a number of bile canalicular transport proteins have been identified that transport bile components out of hepatocytes. One group of these genes, multidrug resistance 1 (mdr1) and mdr2, encode P-glycoproteins. Mice lacking mdr2 expression develop liver disease that appears similar to PNALD. This study investigated the alteration in the expression of these transport proteins during the administration of total parenteral nutrition (TPN).
  
  
  METHODS
  Mice received either physiologic saline and standard chow or TPN. Mice were sacrificed on day 7, and hepatic DNA and RNA content, mRNA expression, and levels of mdr1 and mdr2 proteins were measured.
  
  
  RESULTS
  TPN administration led to a significant (p < .05) decline in mdr2 mRNA expression and an increase in mdr1 mRNA expression. Mdr2 protein expression declined by 66% in the TPN-treated group, and mdr1 protein expression significantly increased by 58%. Histology and biochemical parameters showed no evidence of liver injury. Serum bile acid levels were elevated in the TPN group, suggesting the development of early cholestasis.
  
  
  CONCLUSIONS
  The decline in mdr2 and rise in mdr1 mRNA and protein expression with TPN administration occurred before the development of liver injury but during an early state of cholestasis. This suggests that alterations in mdr gene expression may be a causative factor in the development of PNALD.
authors.affiliation: University of Michigan Medical School, Section of Pediatric Surgery, Department of Surgery, F3970 Mott Children's Hospital, Ann Arbor, Michigan 48109-0245, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tazuke
authors.forename: Irfan
authors.initials: I
authors.lastname: Kiristioglu
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Heidelberger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Eisenbraun
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Teitelbaum
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D001706:Biopsy; D002779:Cholestasis / Q000378:metabolism; D015870:Gene Expression; D019450:Genes, MDR / Q000235:genetics; D008099:Liver / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D012333:RNA, Messenger; C095122:multidrug resistance protein 3; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase