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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 35S-labelled oligodeoxynucleotides, volume of distribution for the phosphorothioate was 0.33 l/kg while the 5' cholesteryl-conjugate oligodeoxynucleotide was 0.12 l/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 publication

DOI

10.3109/10611869509015917

Type

Journal article

Journal

J Drug Target

Publication Date

1995

Volume

2

Pages

477 - 485

Keywords

Animals, Aryl Hydrocarbon Hydroxylases, Base Sequence, Biological Availability, Cholesterol, Cytochrome P-450 CYP2B1, Cytochrome P-450 CYP2E1, Cytochrome P-450 Enzyme System, Drug Delivery Systems, Gene Expression Regulation, Enzymologic, Hexobarbital, Injections, Intraperitoneal, Liver, Male, Microsomes, Liver, Mixed Function Oxygenases, Molecular Sequence Data, Oligonucleotides, Antisense, Oxidoreductases, RNA, Messenger, Rats, Rats, Sprague-Dawley, Sleep, Software, Steroid Hydroxylases, Thionucleotides