PT  - JOURNAL ARTICLE
AU  - Madeline Butler
AU  - Rosanne M. Crooke
AU  - Mark J. Graham
AU  - Kristina M. Lemonidis
AU  - Marilee Lougheed
AU  - Susan F. Murray
AU  - Donna Witchell
AU  - Urs Steinbrecher
AU  - C. Frank Bennett
TI  - Phosphorothioate Oligodeoxynucleotides Distribute Similarly in Class A Scavenger Receptor Knockout and Wild-Type Mice
DP  - 2000 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 489--496
VI  - 292
IP  - 2
4099  - http://jpet.aspetjournals.org/content/292/2/489.short
4100  - http://jpet.aspetjournals.org/content/292/2/489.full
SO  - J Pharmacol Exp Ther2000 Feb 01; 292
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics