A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A

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A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A

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dc.contributor.advisor Croyle, Maria A.
dc.creator Wonganan, Piyanuch
dc.date.accessioned 2010-12-14T17:37:20Z
dc.date.accessioned 2010-12-14T17:37:48Z
dc.date.available 2010-12-14T17:37:20Z
dc.date.available 2010-12-14T17:37:48Z
dc.date.created 2010-08
dc.date.issued 2010-12-14
dc.date.submitted August 2010
dc.identifier.uri http://hdl.handle.net/2152/ETD-UT-2010-08-1969
dc.description.abstract Recombinant adenoviruses, commonly used in gene therapy and vaccine applications, compromise the expression and function of hepatic CYP3A for 14 days. When given with docetaxel (DTX), plasma clearance of DTX (3.38 ± 0.22 l/kg.h) was significantly lower than those given DTX alone (6.41 ± 1.10 l/kg.h). The area under the plasma concentration-time curve of DTX in rats given virus (2,987.37 ± 197.97 ng/ml.h) was significantly greater than those given drug alone (1,666.59 ± 317.04 ng/ml.h). The virus extended the half-life of DTX three-fold. This may explain why adenoviral vectors improve chemotherapy. PEGylation of the virus reduced interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-α), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels in mice and non-human primates. PEGylation dramatically reduced transduction efficiency of virus in the baboon liver and did not alter hepatic transgene expression in the mouse. Unmodified and PEGylated virus (3 x 1012 vp/kg) reduced hepatic CYP3A4 protein by 60% and 40%, respectively 96 hours after virus administration. Catalytic activity was decreased by 55% and 45% with respect to an untreated control by the native and PEGylated viruses respectively. This suggests that changes in hepatic CYP3A during infection is not entirely due to the immune response and these observed effects most likely occur in humans. The effects of adenovirus on hepatic CYP3A expression and function in mice, however, resolved at a faster rate than that in baboons. HC-04 cells are a suitable in vitro model to study virus infection and hepatic CYP3A function. A panel of adenoviruses inhibited CYP3A catalytic activity and induced changes in expression and distribution of retinoid X receptor alpha (RXRα), pregnane X receptor (PXR) and constitutive androstane (CAR) receptors. Virus (1.5 x 1011 vp) inhibited CYP3A in the mouse. When the ability of the virus to bind to integrins was removed, changes in CYP were not detected. Treatment with a RGD peptide, that binds to integrins, reduced CYP3A activity in a manner similar to the virus. Silencing of β3 and β5 integrins also resolved changes in CYP3A activity during infection, suggesting that simple engagement of integrin receptors can initiate changes in CYP3A.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subject Adenovirus
dc.subject Cytochrome P450 3A
dc.title A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A
dc.date.updated 2010-12-14T17:37:49Z
dc.contributor.committeeMember Ghose, Romi
dc.contributor.committeeMember McConville, Jason T.
dc.contributor.committeeMember Van Den Berg, Carla L.
dc.contributor.committeeMember Whitman, Chirstian P.
dc.description.department Pharmacy
dc.type.genre thesis
dc.type.material text
thesis.degree.department Pharmacy
thesis.degree.discipline Pharmacy
thesis.degree.grantor University of Texas at Austin
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy

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