title: Characterization of organic anion-transporting polypeptide (Oatp) 1a1 and 1a4 null mice reveals altered transport function and urinary metabolomic profiles.
abstract: Organic anion-transporting polypeptides (Oatp) 1a1 and 1a4 were deleted by homologous recombination, and mice were characterized for Oatp expression in liver and kidney, transport in isolated hepatocytes, in vivo disposition of substrates, and urinary metabolomic profiles. Oatp1a1 and Oatp1a4 proteins were undetected in liver, and both lines were viable and fertile. Hepatic constitutive messenger RNAs (mRNAs) for Oatp1a4, 1b2, or 2b1 were unchanged in Oatp1a1⁻/⁻ mice, whereas renal Oatp1a4 mRNA decreased approximately 50% (both sexes). In Oatp1a4⁻/⁻ mice, no changes in constitutive mRNAs for other Oatps were observed. Uptake of estradiol-17β-D-glucuronide and estrone-3-sulfate in primary hepatocytes decreased 95 and 75%, respectively, in Oatp1a1⁻/⁻ mice and by 60 and 30%, respectively, in Oatp1a4⁻/⁻ mice. Taurocholate uptake decreased by 20 and 50% in Oatp1a1⁻/⁻ and Oatp1a4⁻/⁻ mice, respectively, whereas digoxin was unaffected. Plasma area under the curve (AUC) for estradiol-17β-D-glucuronide increased 35 and 55% in male and female Oatp1a1⁻/⁻ mice, respectively, with a concurrent 50% reduction in liver-to-plasma ratios. In contrast, plasma AUC or tissue concentrations of estradiol-17β-D-glucuronide were unchanged in Oatp1a4⁻/⁻ mice. Plasma AUCs for dibromosulfophthalein increased nearly threefold in male Oatp1a1⁻/⁻ and Oatp1a4⁻/⁻ mice, increased by 40% in female Oatp1a4⁻/⁻ mice, and were unchanged in female Oatp1a1⁻/⁻ mice. In both lines, no changes in serum ALT, bilirubin, and cholesterol were noted. NMR analyses showed no generalized increase in urinary excretion of organic anions. However, urinary excretion of taurine decreased by 30-40% and was accompanied by increased excretion of isethionic acid, a taurine metabolite generated by intestinal bacteria, suggesting some perturbations in intestinal bacteria distribution.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, New Jersey 08543, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.forename: Nelly
authors.initials: N
authors.lastname: Aranibar
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Youcai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lloyd
authors.initials: L
authors.lastname: Lecureux
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Bhaskaran
authors.forename: Purnima
authors.initials: P
authors.lastname: Khandelwal
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport / Q000235:genetics; D015153:Blotting, Western; D004958:Estradiol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D004970:Estrone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects; D059765:Homologous Recombination; D007513:Isethionic Acid / Q000652:urine; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013654:Taurine / Q000652:urine; D013656:Taurocholic Acid / Q000493:pharmacokinetics
chemical_list: D027361:Organic Anion Transporters; D012333:RNA, Messenger; C025483:estradiol-17 beta-glucuronide; D013654:Taurine; D004970:Estrone; D004958:Estradiol; D013656:Taurocholic Acid; D007513:Isethionic Acid; C017296:estrone sulfate