Impact of transgene expression on drug metabolism following systemic adenoviral vector administration

The Journal of Gene Medicine
Shellie M CallahanM A Croyle

Abstract

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. Sprague-Dawley rats were given 5.7 x 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. Administration of Epo did not alter CYP3A2 activity, but induced RNA levels by a factor of 2 at 4 and 14 days (P< or =0.01). This vector suppressed CYP2C11 activity levels by 45% at 1 day (P< or =0.05) and RNA levels throughout the study period (P< or =0.05). The Null vector suppressed CYP3A2 activity by 36, 63, 34, and 45% at 0.25, 1, 4 and 14 days, respectively (P< or =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< or =0.05). In contrast, Adl...Continue Reading

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Citations

Sep 9, 2010·Molecular Pharmaceutics·Piyanuch WongananMaria A Croyle
Dec 28, 2007·Journal of Virological Methods·Shellie M CallahanMaria A Croyle
Feb 13, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kristina Jonsson-SchmunkMaria A Croyle
Jun 19, 2007·The Journal of Biological Chemistry·Sho AkaiTsuyoshi Yokoi
Oct 20, 2012·Health Economics, Policy, and Law·Daniel Callahan
Mar 6, 2021·Expert Review of Vaccines·Kristina Jonsson-SchmunkMaria A Croyle

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