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Research ArticleArticle

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

Vikram Arora, Melissa L. Cate, Chandramallika Ghosh and Patrick L. Iversen
Drug Metabolism and Disposition July 2002, 30 (7) 757-762; DOI: https://doi.org/10.1124/dmd.30.7.757
Vikram Arora
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Melissa L. Cate
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Chandramallika Ghosh
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Patrick L. Iversen
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Abstract

Antisense phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thus preventing translation. Inhibition of cytochrome P450 (P450) 3A4 expression was examined in primary human hepatocytes from 11 donors and in Caco-2 cells (stably transfected with CYP3A4 cDNA on an extrachromosomal vector) by evaluating the metabolism of substrate 7-benzyloxy-4-[trifluoromethyl]-coumarin and Western immunoblot analysis. Cellular uptake of PMO was confirmed in both cell systems using fluorescein-labeled PMOs. Three antisense PMO sequences and two control PMO sequences were tested. AVI-4557, a 20-mer PMO with the sequence 5′-CTGGGATGAGAGCCATCACT-3′ was selected as the optimal agent. AVI-4557 inhibited expression of CYP3A4 in Caco-2/h3A4 cells by 64% at 24 h following administration of 2.8 μM by an assisted delivery protocol. Inhibition of CYP3A activity was observed in primary human hepatocytes after 24 h exposure to AVI-4557 by an average of 32 ± 11%. Furthermore, AVI-4557 exposure resulted in a sequence-dependent inhibition of cyclophosphamide-related cytocidal activity and a sequence-dependent induction of paclitaxel-related cytocidal activity in both cell types. Finally, the cytocidal activity of cisplatin was not affected with AVI-4557 treatment in either cell type. These studies indicate AVI-4557 is an effective and specific inhibitor of CYP3A4 expression.

Footnotes

  • ↵1 Current address: North American Science Associates, Northwood, OH.

  • This work was supported with funds from the National Institutes of Health (Grant GM54871) and AVI BioPharma, Inc. A portion of this work was presented at the 2001 Society of Toxicology Annual Meeting; 2001 Mar 25–29; San Francisco, CA.

  • Abbreviations used are::
    P450
    cytochromes P450
    PMO
    phosphorodiamidate morpholino oligomer
    SD
    Gene Tools' special delivery protocol
    cisplatinum
    cis-platinum(II)-diamine dichloride
    cyclophosphamide
    cyclophosphamide monohydrate
    BFC
    7-benzyloxy-4-[trifluoromethyl]-coumarin
    HFC
    7-hydroxy-4-[trifluoromethyl]-coumarin
    F-PMO
    PMO labeled with carboxy-fluorescein on the 5′ end
    SNP
    single nucleotide polymorphisms
    • Received February 21, 2002.
    • Accepted March 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

Vikram Arora, Melissa L. Cate, Chandramallika Ghosh and Patrick L. Iversen
Drug Metabolism and Disposition July 1, 2002, 30 (7) 757-762; DOI: https://doi.org/10.1124/dmd.30.7.757

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Research ArticleArticle

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

Vikram Arora, Melissa L. Cate, Chandramallika Ghosh and Patrick L. Iversen
Drug Metabolism and Disposition July 1, 2002, 30 (7) 757-762; DOI: https://doi.org/10.1124/dmd.30.7.757
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