Recombinant adenoviral-meditated alterations of cytochrome P450 3A2 and 2C11

Date
2005
Authors
Callahan, Shellie Marie
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Recombinant adenovirus serotype 5 (Ad) is a key vector extensively employed in gene therapy clinical trials and vaccine development protocols. Although this vector has a natural tropism for the liver, there is limited understanding of how Ad infection affects one of the primary hepatic processes, drug metabolism. Preliminary data investigating the effect of a single dose of 5.7 x 1012 adenovirus particles/kilogram on the hepatic cytochrome P450 enzyme system (CYP) revealed not only that significant suppression occurs following systemic administration, but also that enzymatic activity remains suppressed for 14 days. In addition to the vector dose, various components of the virus (transgene, virus gene expression and capsid-receptor interactions) viii could be responsible for the observed suppression in hepatic CYP. Investigation of treatment (5.7 x 1010-5.7 x 1012 vp/kg) of a recombinant vector expressing a non-therapeutic transgene significantly suppressed CYP3A2 expression (mean value of 39%) and function (mean value of 41%) four days after administration. Doses in the range of 5.7 x 106-5.7 x 109 vp/kg did not alter CYP3A2 expression or function, but significantly increased CYP2C11 one day after administration. Expression levels (mean value of 88%) and activity levels (mean value of 93%) were markedly increased. Doses of vectors expressing self transgenes and no transgene revealed that CYP is altered regardless of the transgene cassette used. Treatment with the Null vector, a vector without a transgene cassette, significantly altered CYP3A2 activity throughout the duration of the study (14 days) and CYP2C11 activity at early time points (6 and 24 hours). In addition, modifications at the molecular and macromolecular level do not eliminate aberrations in CYP following Ad administration. Treatment with an adenoviral vector lacking all viral genes markedly suppressed both CYP isoforms, at the transcriptional and translational level, for 14 days. The data presented here suggest that the binding of Ad to cell surface receptors and subsequent internalization of the virion significantly alters posttranslational CYP function, possibly through altered signal transduction pathways. In addition these studies show that shifts in cellular machinery to support the production of the transgene product, and not the transcription of viral genes, also repress CYP transcription.

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