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重组腺病毒载体的分子和大分子改变并不能解决感染期间肝脏药物代谢的变化。

Molecular and macromolecular alterations of recombinant adenoviral vectors do not resolve changes in hepatic drug metabolism during infection.

作者信息

Callahan Shellie M, Wonganan Piyanuch, Croyle Maria A

机构信息

College of Pharmacy, Division of Pharmaceutics, The University of Texas at Austin, Austin, TX, USA.

出版信息

Virol J. 2008 Sep 30;5:111. doi: 10.1186/1743-422X-5-111.

DOI:10.1186/1743-422X-5-111
PMID:18826641
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2565663/
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 x 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 <or= 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 <or= 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 <or= 0.05). CYP3A2 remained suppressed (34%, p <or= 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25-50% for 14 days (p <or= 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.

摘要

在本报告中，我们检验了以下假设：长期病毒诱导的细胞色素P450（CYP）改变源于病毒引发的变化，这些变化可能与免疫反应无关。在给雄性斯普拉格-道利大鼠以5.7×10¹²病毒颗粒（vp）/kg的剂量施用几种不同的重组腺病毒后0.25、1、4和14天，评估了人CYP3A4的相关物CYP3A2以及对炎症介质有反应的CYP2C11的酶活性、蛋白质表达和mRNA水平。含有所有病毒基因的野生型腺病毒在6小时内分别将CYP3A2和2C11的活性抑制了37%和39%。到14天时，水平降至对照的67%（CYP3A2）和79%（CYP2C11）（p≤0.01）。去除了所有病毒基因的辅助依赖型腺病毒在6小时内抑制了CYP3A2（43%）和CYP2C11（55%）。此时CYP3A2仍被显著抑制（47%，14天，p≤0.01），而CYP2C11恢复到基线水平。用免疫原性较低的聚乙二醇化腺病毒处理6小时后，CYP3A2和2C11分别降低了45%和42%（p≤0.05）。CYP3A2在14天内仍被抑制（34%，p≤0.05），而CYP2C11恢复。灭活病毒在14天内将CYP3A2活性抑制了25%-50%（p≤0.05）。CYP2C11受到类似影响，但在第14天恢复。微阵列和体外研究表明，病毒感染早期引发的细胞信号通路变化导致了CYP的改变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/2e67ae0118f0/1743-422X-5-111-10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/5c5e66400d27/1743-422X-5-111-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/bfded41bcdcc/1743-422X-5-111-2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/5ce3b87338b8/1743-422X-5-111-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/10719777951b/1743-422X-5-111-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/3c999ca316ba/1743-422X-5-111-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/e9d85f1f1823/1743-422X-5-111-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/ae1b84a72d1b/1743-422X-5-111-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/2e67ae0118f0/1743-422X-5-111-10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/5c5e66400d27/1743-422X-5-111-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/bfded41bcdcc/1743-422X-5-111-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/d9bade6fbf99/1743-422X-5-111-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/b430a2a0cf55/1743-422X-5-111-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/5ce3b87338b8/1743-422X-5-111-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/10719777951b/1743-422X-5-111-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/3c999ca316ba/1743-422X-5-111-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/e9d85f1f1823/1743-422X-5-111-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/ae1b84a72d1b/1743-422X-5-111-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d703/2565663/2e67ae0118f0/1743-422X-5-111-10.jpg

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