Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model
Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model
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大鼠肾病模型中肠和肝细胞色素 P450 3A 下调对环孢素 A 吸收增加的贡献
DOI：
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发表时间：
2008
影响因子：
3.5
通讯作者：
M. Majima
中科院分区：
文献类型：
--
作者：
T. Fujita;S. Yasuda;Yuji Kamata;Kazumi Fujita;Y. Ohtani;Y. Kumagai;M. Majima
本研究探讨了在大鼠肾病模型中，肠和肝细胞色素P450 3A（CYP 3A）和多药耐药转运蛋白1（Mdr 1）的调节变化对环孢素A（CsA）吸收的贡献。还测量了白细胞介素（IL）-6。以20 mg/100 g的剂量静脉给予嘌呤霉素氨基糖苷。在肾病发生后，从上、中肠和肝脏解剖组织样品以测量mRNA和蛋白质的表达水平。CsA以0.5 mg/100 g的剂量给药到上肠和中肠的闭合环中。从下腔静脉（IVC）和门静脉采血，直至给药后30 min。CYP 3A的表达水平显着下降，而Mdr 1表现出很大的个体间差异的所有组织中的肾病大鼠。CsA的血浆浓度达到较高的水平，在肾病比对照组大鼠，并高于从门静脉和IVC中肠上部时，给药。肾病大鼠尿中IL-6升高。总之，在肾病模型中肠和肝CYP 3A下调，伴随IL-6水平升高。对于Mdr 1的调节，未获得一致的结果。总之，这些研究结果表明，CYP 3A在上肠和肝脏中的下调主要有助于增加CsA的吸收，而Mdr 1在该大鼠肾病模型中的贡献较小。
This study examined the contribution of changes in regulation of intestinal and hepatic cytochrome P450 3A (CYP3A) and multidrug resistance transporter 1 (Mdr1) to absorption of cyclosporine A (CsA) in a rat nephrosis model. Interleukin (IL)-6 was also measured. Puromycin aminonucleoside at a dose of 20 mg/100 g was administered intravenously. Tissue samples were dissected out from the upper and middle intestines and liver after development of nephrosis to measure the expression levels of mRNA and protein. CsA at a dose of 0.5 mg/100 g was administered into a closed loop of the upper and middle intestines. Blood from the inferior vena cava (IVC) and portal vein was taken until 30 min after administration. The expression levels of CYP3A decreased markedly, whereas those of Mdr1 showed large interindividual variations for all of the tissues in the nephrotic rats. Plasma concentrations of CsA reached higher levels in the nephrotic than in the control rats and were higher when administered from the upper than the middle intestine in both the portal vein and IVC. IL-6 increased in urine in the nephrotic rats. In summary, intestinal and hepatic CYP3A were down-regulated in the nephrosis model accompanying the increased levels of IL-6. Consistent results were not obtained for the regulation of Mdr1. In conclusion, these findings suggest that the down-regulation of CYP3A in the upper intestine and liver predominantly contributes to the increase in CsA absorption, and Mdr1 showed less contribution in this rat nephrosis model.
影响因子：
1.8
作者：
BergCandolfi, M;Candolfi, E;Benet, LZ
通讯作者：
Benet, LZ
体内内毒素对三种主要大鼠肝细胞色素 P450S 表达的下调与一氧化氮的产生无关。
DOI：
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发表时间：
1998
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Sewer,MB;Morgan,ET
通讯作者：
Morgan,ET
影响因子：
3.9
作者：
Cherrington, NJ;Slitt, AL;Klaassen, CD
通讯作者：
Klaassen, CD