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Strathprints serves world leading Open Access research by the University of Strathclyde, including research by the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), where research centres such as the Industrial Biotechnology Innovation Centre (IBioIC), the Cancer Research UK Formulation Unit, SeaBioTech and the Centre for Biophotonics are based.

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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.