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Impact of transgene expression on drug metabolism following systemic adenoviral vector administration
Author(s) -
Callahan Shellie M.,
Boquet Michael P.,
Ming Xin,
Brunner Lane J.,
Croyle Maria A.
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.884
Subject(s) - transgene , cytochrome p450 , systemic administration , biology , medicine , messenger rna , gene isoform , viral vector , endocrinology , pharmacology , in vivo , andrology , metabolism , recombinant dna , gene , biochemistry , microbiology and biotechnology
Background Systemic administration of a first‐generation adenovirus expressing E. coli beta‐galactosidase (AdlacZ) alters expression and function of two hepatic drug‐metabolizing enzymes, cytochrome P450 (CYP) 3A2 and 2C11, for 14 days. The objective of these studies was to determine how the transgene cassette influences CYP expression and function. Methods Sprague‐Dawley rats were given 5.7 × 10 12 viral particles (vp)/kg of either: AdlacZ, Ad expressing murine erythropoietin (Epo), Ad without a transgene (Null), or phosphate‐buffered saline (Vehicle). Hepatic CYP protein expression, activity, mRNA and alanine aminotransferase (ALT) levels were analyzed 0.25, 1, 4, and 14 days following a single intravenous injection. Results Administration of Epo did not alter CYP3A2 activity, but induced RNA levels by a factor of 2 at 4 and 14 days ( P ⩽0.01). This vector suppressed CYP2C11 activity levels by 45% at 1 day ( P ⩽0.05) and RNA levels throughout the study period ( P ⩽0.05). The Null vector suppressed CYP3A2 activity by 36, 63, 34, and 45% at 0.25, 1, 4 and 14 days, respectively ( P ⩽0.05). CYP2C11 activity was suppressed 1 day after administration (41%) and RNA levels were suppressed at 6 h (53%) and 1 day (36%, P ⩽0.05). In contrast, AdlacZ suppressed both CYP3A2 and 2C11 at all time points. Conclusions The immunogenic and biological nature of the transgene cassette can influence changes in CYP3A2, but not the 2C11 isoform. The shift in transcription and translation of protein for maintenance of physiologic homeostasis to production of viral proteins and transgene product and their associated toxicity during viral infection may explain our observations. Copyright © 2006 John Wiley & Sons, Ltd.