Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid

Toxicology. 2013 Apr 5;306:108-13. doi: 10.1016/j.tox.2013.02.009. Epub 2013 Feb 19.

Abstract

The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / biosynthesis*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Blotting, Western
  • Caprylates / toxicity*
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P450 Family 4
  • Fluorescent Antibody Technique, Indirect
  • Fluorocarbons / toxicity*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Kidney / drug effects*
  • Kidney / enzymology
  • Kidney / metabolism
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Organ Size / drug effects
  • PPAR alpha / agonists
  • PPAR alpha / metabolism
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Transfection

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Caprylates
  • Cyp4a14 protein, mouse
  • Fluorocarbons
  • Neoplasm Proteins
  • PPAR alpha
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System
  • perfluorooctanoic acid
  • Cytochrome P450 Family 4