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Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo

Desjardins, J. and Mata, J. and Brown, T. and Graham, D. and Zon, G. and Iversen, P. (1995) Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo. Journal of Drug Targeting, 2 (6). pp. 477-485. ISSN 1061-186X

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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.

Item type: Article
ID code: 948
Keywords: cholesteryl-conjugated, CYP2B1, CYP450, oligodeoxynucleotides, phosphorothioate, Chemistry, Therapeutics. Pharmacology
Subjects: Science > Chemistry
Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Pure and Applied Chemistry
Related URLs:
    Depositing user: Mr Derek Boyle
    Date Deposited: 04 May 2006
    Last modified: 12 Mar 2012 10:36
    URI: http://strathprints.strath.ac.uk/id/eprint/948

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