title: Loss of organic anion transporting polypeptide 1a1 increases deoxycholic acid absorption in mice by increasing intestinal permeability.
abstract: Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)α/β, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Iván L
authors.initials: IL
authors.lastname: Csanaky
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002853:Chromatography, Liquid; D003840:Deoxycholic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D003840:Deoxycholic Acid; D027701:Organic Cation Transport Proteins; C572127:SLCO1A1 protein, mouse