Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1

DOI Web Site 8 Citations
  • Yan Shu
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Maya K. Leabman
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Bo Feng
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Lara M. Mangravite
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Conrad C. Huang
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Doug Stryke
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Michiko Kawamoto
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Susan J. Johns
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Joseph DeYoung
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Elaine Carlson
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Thomas E. Ferrin
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Ira Herskowitz
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448
  • Kathleen M. Giacomini
    Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143-0446; Genomics Core Facility, Program in Human Genetics, University of California, San Francisco, CA 94143-0984; and Department of Biochemistry and Biophysics, and Program in Human Genetics, University of California, San Francisco, CA 94143-0448

Abstract

<jats:p> The organic cation transporter, OCT1, is a major hepatic transporter that mediates the uptake of many organic cations from the blood into the liver where the compounds may be metabolized or secreted into the bile. Because OCT1 interacts with a variety of structurally diverse organic cations, including clinically used drugs as well as toxic substances (e.g., <jats:italic>N</jats:italic> -methylpyridinium, MPP <jats:sup>+</jats:sup> ), it is an important determinant of systemic exposure to many xenobiotics. To understand the genetic basis of extensive interindividual differences in xenobiotic disposition, we functionally characterized 15 protein-altering variants of the human liver organic cation transporter, OCT1, in <jats:italic>Xenopus</jats:italic> oocytes. All variants that reduced or eliminated function (OCT1-R61C, OCT1-P341L, OCT1-G220V, OCT1-G401S, and OCT1-G465R) altered evolutionarily conserved amino acid residues. In general, variants with decreased function had amino acid substitutions that resulted in more radical chemical changes (higher Grantham values) and were less evolutionarily favorable (lower <jats:sc>blosum</jats:sc> 62 values) than variants that maintained function. A variant with increased function (OCT1-S14F) changed an amino acid residue such that the human protein matched the consensus of the OCT1 mammalian orthologs. Our results indicate that changes at evolutionarily conserved positions of OCT1 are strong predictors of decreased function and suggest that a combination of evolutionary conservation and chemical change might be a stronger predictor of function. </jats:p>

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