Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo

J. Desjardins, J. Mata, T. Brown, D. Graham, G. Zon, P. Iversen

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Abstract

5' cholesteryl-conjugated phosphorothioate oligodeoxynucleotides with sequence complementary to the rat CYP2B1 mRNA were evaluated in adult male Sprague-Dawley rats for their pharmacokinetic properties, toxicity, and ability to modulate CYP2B1 expression in vivo. Following intraperitoneal administration of S-35-labelled oligodeoxynucleotides, volume of distribution for the phosphorothioate was 0.33 1/kg while the 5' cholesteryl-conjugate oligodeoxynucleotide was 0.12 1/kg. The elimination half-life was 23.2 and 55.4 hrs for cholesteryl modified and unmodified oligodeoxynucleotides, respectively. Cholesteryl-conjugate oligodeoxynucleotide toxicity was detected at a dose of 1.0 mg/kg and consisted primarily of midzonal liver cell enlargement and increased total RNA. Hexobarbital sleep times, a measure of CYP2B1 enzyme activity in vivo, increased from 21.9 minutes in saline-treated animals to 29.5 minutes in cholesterol oligodeoxynucleotide-treated animals. A significant decrease in liver microsomal pentoxyresorufin O-dealkylase enzyme activity, a CYP2B1/2 specific assay, was observed but not a change in p-nitrophenol hydroxylase activity, a specific CYP2E1 assay. These data indicate that in vivo modulation of the CYP2B1 gene can be accomplished with synthetic phosphorothioate oligodeoxynucleotides in a sequence-specific manner. Further, cholesteryl conjugation to the 5' end of the oligodeoxynucleotide enhanced potency despite lesser bioavailability.
Original languageEnglish
Pages (from-to)477-485
Number of pages8
JournalJournal of Drug Targeting
Volume2
Issue number6
Publication statusPublished - 1995

Keywords

  • cholesteryl-conjugated
  • CYP2B1
  • CYP450
  • oligodeoxynucleotides
  • phosphorothioate

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