Abstract
In this report we test the hypothesis that long-term virus-induced alterations in CYP occur from changes initiated by the virus that may not be related to the immune response. Enzyme activity, protein expression and mRNA of CYP3A2, a correlate of human CYP3A4, and CYP2C11, responsive to inflammatory mediators, were assessed 0.25, 1, 4, and 14 days after administration of several different recombinant adenoviruses at a dose of 5.7 × 1012 virus particles (vp)/kg to male Sprague Dawley rats. Wild type adenovirus, containing all viral genes, suppressed CYP3A2 and 2C11 activity by 37% and 39%, respectively within six hours. Levels fell to 67% (CYP3A2) and 79% (CYP2C11) of control by 14 days (p ≤ 0.01). Helper-dependent adenovirus, with all viral genes removed, suppressed CYP3A2 (43%) and CYP2C11 (55%) within six hours. CYP3A2 remained significantly suppressed (47%, 14 days, p ≤ 0.01) while CYP2C11 returned to baseline at this time. CYP3A2 and 2C11 were reduced by 45 and 42% respectively 6 hours after treatment with PEGylated adenovirus, which has a low immunological profile (p ≤ 0.05). CYP3A2 remained suppressed (34%, p ≤ 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25–50% for 14 days (p ≤ 0.05). CYP2C11 was affected similar manner but recovered by day 14. Microarray and in vitro studies suggest that changes in cellular signaling pathways initiated early in virus infection contribute to changes in CYP.
Highlights
Hepatic cytochrome P450 (CYP) enzymes play a central role in the metabolism and clearance of many naturally occurring biological substances, drugs and environmental toxins [1,2]
Fourteen days after administration CYP3A1/2 protein remained significantly suppressed without evidence of recovery in animals treated with wild type adenovirus 5 (WT) (31% of control) AdlacZ (37%) and helper-dependent virus expressing beta-galactosidase (HDAd) (29%) (Figure 1D, p ≤ 0.01)
Mean relative intensities of CYP3A2 mRNA and representative agarose gels of PCR products 0.25 (A), 1 (B), 4 (C), and 14 (D) days after treatment with wild type adenovirus 5 (WT), first generation recombinant adenovirus expressing E. coli beta-galactosidase (AdlacZ), PEGylated AdlacZ, (PEGAd), helper-dependent virus expressing beta-galactosidase (HDAd), or inactivated AdlacZ (UVAd). mRNA levels are reported as band densities of gene-specific RT-PCR products with respect to the density of products from an internal control (18S rRNA) in arbitrary units
Summary
Hepatic cytochrome P450 (CYP) enzymes play a central role in the metabolism and clearance of many naturally occurring biological substances, drugs and environmental toxins [1,2]. Their diversity, expression and function may be modified by these substrates [3,4]. Numerous clinical reports have described altered pharmacokinetic and toxicity profiles of drugs during infection or inflammation [5,6] In these instances, the activity and expression of CYP is downregulated, leading to ineffective treatment regimens, unexpected adverse reactions and in, some cases, drug-drug interactions [7,8]. The expression and function of these isoforms, selected for their predominance in drug metabolism (page number not for citation purposes)
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