Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.
LanguageEnglish
Pages477-485
Number of pages8
JournalJournal of Drug Targeting
Volume2
Issue number6
Publication statusPublished - 1995

Fingerprint

Cytochrome P-450 CYP2B1
Oligodeoxyribonucleotides
Cell Enlargement
Hexobarbital
Cytochrome P-450 CYP2E1
Aptitude
Liver
Enzymes
Mixed Function Oxygenases
Biological Availability
Sprague Dawley Rats
Half-Life
Sleep
Pharmacokinetics
Cholesterol
RNA
Messenger RNA

Keywords

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

Cite this

Desjardins, J. ; Mata, J. ; Brown, T. ; Graham, D. ; Zon, G. ; Iversen, P. / Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo. In: Journal of Drug Targeting. 1995 ; Vol. 2, No. 6. pp. 477-485.
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Desjardins, J, Mata, J, Brown, T, Graham, D, Zon, G & Iversen, P 1995, 'Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo' Journal of Drug Targeting, vol. 2, no. 6, pp. 477-485.

Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo. / Desjardins, J.; Mata, J.; Brown, T.; Graham, D.; Zon, G.; Iversen, P.

In: Journal of Drug Targeting, Vol. 2, No. 6, 1995, p. 477-485.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cholesteryl-conjugated phosphorthioate oligodeoxynucleotides modulate CYP2B1 expression in vivo

AU - Desjardins, J.

AU - Mata, J.

AU - Brown, T.

AU - Graham, D.

AU - Zon, G.

AU - Iversen, P.

PY - 1995

Y1 - 1995

N2 - 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.

AB - 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.

KW - cholesteryl-conjugated

KW - CYP2B1

KW - CYP450

KW - oligodeoxynucleotides

KW - phosphorothioate

M3 - Article

VL - 2

SP - 477

EP - 485

JO - Journal of Drug Targeting

T2 - Journal of Drug Targeting

JF - Journal of Drug Targeting

SN - 1061-186X

IS - 6

ER -