Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats
Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats
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DOI：
10.1124/dmd.32.1.20
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发表时间：
2004-01-01
影响因子：
3.9
通讯作者：
Piquette-Miller, M
中科院分区：
文献类型：
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作者：
Kalitsky-Szirtes, J;Shayeganpour, A;Piquette-Miller, M
感染和炎症会抑制肝脏中几种药物转运体和药物代谢酶的表达和活性。在肠道中，细胞色素P450 3A （CYP3A）、p -糖蛋白（PGP/mdr1）和多药耐药相关蛋白2 （MRP2）是许多临床重要药物吸收的重要障碍；因此，在炎症中检测了这些蛋白的表达和活性。内毒素处理大鼠和对照大鼠（n = 8）装在Ussing腔中，24 h分离空肠段，测定其转运和代谢。在存在和不存在抑制剂的情况下，测量h -3-地高辛、5-羧基荧光素（5-CF）、胺碘酮（AM）和7-苯氧喹啉（7-BQ）在90分钟内的转运和代谢。逆转录聚合酶链反应测定mRNA水平。与对照组相比，lps处理大鼠空肠中mdr1a和mrp2 mRNA水平显著降低约50%。观察到地高辛、AM和5-CF的基底外侧->端外排相应减少，导致这些化合物的基底外侧->吸收显著增加。LPS组肠道CYP3A mRNA水平和CYP3A介导的7-BQ和AM代谢也降低了约50% ~ 70% （p < 0.05）。甘露醇渗透性和乳酸脱氢酶释放没有改变。这些研究表明，内毒素诱导的炎症导致大鼠肠道中PGP、mrp2和CYP3A的表达和活性降低，从而导致其底物的肠道运输和代谢发生相应的变化。因此，感染和炎症性疾病可能通过改变肠道中药物转运体和代谢酶的表达和活性来施加药物生物利用度的变异性。
Infection and inflammation impose a suppression in the expression and activity of several drug transporters and drug-metabolizing enzymes in liver. In the intestine, cytochrome P450 3A (CYP3A), P-glycoprotein (PGP/mdr1), and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs; thus, the expression and activity of these proteins were examined in inflammation. Transport and metabolism were determined in jejunum segments isolated at 24 h from endotoxin-treated or control rats (n = 8) mounted in Ussing chambers. Transport and metabolism of H-3-digoxin, 5-carboxyfluorescein (5-CF), amiodarone (AM), and 7-benzyloxyquinoline (7-BQ) were measured for 90 min in the presence and absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. As compared with controls, levels of mdr1a and mrp2 mRNA were significantly decreased by approximately 50% in the jejunum of LPS-treated rats. Corresponding reductions in the basolateral-->apical efflux of digoxin, AM, and 5-CF were observed, resulting in significant increases in the apical-->basolateral absorption of these compounds. Intestinal CYP3A mRNA levels and CYP3A-mediated metabolism of 7-BQ and AM were also decreased by approximately 50 to 70% (p < 0.05) in the LPS group. Mannitol permeability and lactate dehydrogenase release were not altered. These studies indicate that endotoxin-induced inflammation imposes a reduction in the intestinal expression and activity of PGP, mrp2, and CYP3A in rats, which elicits corresponding changes in the intestinal transport and metabolism of their substrates. Hence, infection and inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters and metabolic enzymes.