Considerations for use of recombinant adenoviral vectors: Dose effect on hepatic cytochromes P450
Considerations for use of recombinant adenoviral vectors: Dose effect on hepatic cytochromes P450
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DOI：
10.1124/jpet.104.075374
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Croyle, MA
中科院分区：
文献类型：
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作者：
Callahan, SM;Ming, X;Croyle, MA
重组腺病毒 (Ad) 血清型 5 是常用于基因递送的载体。尽管该载体对肝脏具有天然趋向性，但对于 Ad 给药如何影响主要肝脏过程之一（药物代谢）的了解有限。研究了模型重组腺病毒载体全身给药对两种肝细胞色素 P450 (P450) 酶 CYP3A2 和 2C11 的影响。 Sprague-Dawley 大鼠接受六种载体剂量中的一种治疗，剂量范围为 5.7 x 10(6) 至 5.7 x 10(12) 病毒颗粒 (vp)/kg。在 14 天内测量肝脏 P450 蛋白表达、催化活性和 mRNA 水平。在研究期间，Ad给药（5.7 x 10(10) - 5.7 x 10(12) vp/kg）减少了CYP3A2。给予5.7 x 10(12) vp/kg后6小时，CYP3A2活性和mRNA水平分别被抑制45%和65%（P小于或等于0.01）。这种情况在整个研究过程中持续存在，到 14 天时水平分别降至对照的 36% 和 45%（P 小于或等于 0.01）。在此剂量范围内，CYP2C11 也检测到类似的趋势。与用盐水处理的动物相比，给予 5.7 x 10(6)、5.7 x 10(8) 和 5.7 x 10(9) vp/kg Ad 显着增加 CYP2C11 蛋白表达分别达 86、71 和 107%，活性分别增加 110、118 和 53%（P 小于或等于 0.01）。这些结果清楚地表明，单剂量的腺病毒在较长时间内显着改变关键药物代谢酶，应在临床试验方案的设计和实施中进一步研究。
Recombinant adenovirus (Ad) serotype 5 is a vector commonly used for gene delivery. Although this vector has a natural tropism for the liver, there is a limited understanding of how Ad administration affects one of the primary hepatic processes, drug metabolism. The effects of systemic administration of a model recombinant adenoviral vector on two hepatic cytochrome P450 (P450) enzymes, CYP3A2 and 2C11, were investigated. Sprague-Dawley rats were treated with one of six vector doses, ranging from 5.7 x 10(6) to 5.7 x 10(12) virus particles (vp)/kg. Hepatic P450 protein expression, catalytic activity, and mRNA levels were measured over 14 days. Ad administration (5.7 x 10(10) - 5.7 x 10(12) vp/kg) reduced CYP3A2 over the duration of the study. Six hours after administration of 5.7 x 10(12) vp/kg, CYP3A2 activity and mRNA levels were suppressed by 45 and 65%, respectively (P less than or equal to 0.01). This continued throughout the study with levels dropping to 36 and 45% of controls by 14 days, respectively ( P less than or equal to 0.01). A similar trend was detected for CYP2C11 within this dosing range. Administration of 5.7 x 10(6), 5.7 x 10(8), and 5.7 x 10(9) vp/kg of Ad significantly increased both CYP2C11 protein expression by 86, 71, and 107% and activity 110, 118, and 53%, respectively, above those of animals treated with saline ( P less than or equal to 0.01). These results clearly indicate that a single dose of adenovirus significantly alters key drug metabolizing enzymes for an extended period of time and should be investigated further in the context of the design and implementation of clinical trial protocols.