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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phosphorothioate Oligodeoxynucleotides Distribute Similarly in Class A Scavenger Receptor Knockout and Wild-Type Mice

Madeline Butler, Rosanne M. Crooke, Mark J. Graham, Kristina M. Lemonidis, Marilee Lougheed, Susan F. Murray, Donna Witchell, Urs Steinbrecher and C. Frank Bennett
Journal of Pharmacology and Experimental Therapeutics February 2000, 292 (2) 489-496;
Madeline Butler
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Rosanne M. Crooke
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Mark J. Graham
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Kristina M. Lemonidis
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Marilee Lougheed
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Susan F. Murray
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Donna Witchell
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Urs Steinbrecher
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C. Frank Bennett
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Abstract

It has been suggested that binding of phosphorothioate oligodeoxynucleotides (P=S ODNs) to macrophage scavenger receptors (SR-AI/II) is the primary mechanism of P=S ODN uptake into cells in vivo. To address the role of scavenger receptors in P=S ODN distribution in vivo, several pharmacokinetic and pharmacological parameters were compared in tissues from scavenger receptor knockout mice (SR-A−/−) and their wild-type counterparts after i.v. administration of 5- and 20-mg/kg doses of P=S ODN. With an antibody that recognizes P=S ODN, no differences in cellular distribution or staining intensity in livers, kidneys, lungs, or spleens taken from SR-A−/− versus wild-type mice could be detected at the histological level. There were no significant differences in P=S ODN concentrations in these organs as measured by capillary gel electrophoresis as well, although the concentration of P=S ODN in isolated Kupffer cells from livers of SR-A−/− mice was 25% lower than that in Kupffer cells from wild-type mice. Furthermore, a P=S ODN targeting murine A-raf reduced A-raf RNA levels to a similar extent in livers from SRA−/− (92.8%) and wild-type (88.3%) mice. Finally, in vitro P=S ODN uptake studies in peritoneal macrophages from SR-A−/− versus wild-type mice indicate that other high- and low-affinity uptake mechanisms predominate. Taken as a whole, our data suggest that, although there may be some contribution to P=S ODN uptake by the SR-AI/II receptor, this mechanism alone cannot account for the bulk of P=S ODN distribution into tissues and cells in vivo, including macrophages.

Footnotes

  • Send reprint requests to: Madeline Butler, ISIS Pharmaceuticals, 2292 Faraday Ave., Carlsbad, CA 92008. E-mail:mbutler{at}isisph.com

  • ↵1 Current address: Department of Medicine, the University of British Columbia, Vancouver, British Columbia V5Z4E3, Canada.

  • Abbreviations:
    P=S ODN
    phosphorothioate oligodeoxynucleotides
    SR-AI/II
    macrophage scavenger receptors
    SR-A−/−
    macrophage scavenger receptor knockout mice
    CGE
    quantitative capillary gel eletrophoresis
    LDL
    low-density lipoproteins
    Ox-LDL
    oxidized LDL
    Ac-LDL
    acetylated LDL
    poly(I)
    polyinosinic acid
    malBSA
    maleylated BSA
    SPE
    solid-phase extraction
    • Received August 11, 1999.
    • Accepted October 6, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 2
1 Feb 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phosphorothioate Oligodeoxynucleotides Distribute Similarly in Class A Scavenger Receptor Knockout and Wild-Type Mice

Madeline Butler, Rosanne M. Crooke, Mark J. Graham, Kristina M. Lemonidis, Marilee Lougheed, Susan F. Murray, Donna Witchell, Urs Steinbrecher and C. Frank Bennett
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 489-496;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phosphorothioate Oligodeoxynucleotides Distribute Similarly in Class A Scavenger Receptor Knockout and Wild-Type Mice

Madeline Butler, Rosanne M. Crooke, Mark J. Graham, Kristina M. Lemonidis, Marilee Lougheed, Susan F. Murray, Donna Witchell, Urs Steinbrecher and C. Frank Bennett
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 489-496;
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