Induction of multidrug resistance-1 and cytochrome P450 mRNAs in human mononuclear cells by rifampin.
Induction of multidrug resistance-1 and cytochrome P450 mRNAs in human mononuclear cells by rifampin.
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DOI：
10.1124/dmd.30.1.20
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发表时间：
2002
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影响因子：
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通讯作者：
A. Asghar;J. Gorski;B. Haehner‐Daniels;Stephen D. Hall
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文献类型：
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作者：
A. Asghar;J. Gorski;B. Haehner‐Daniels;Stephen D. Hall
逆转录-聚合酶链反应（RT-PCR）和定量，竞争性RT-PCR检测利福平诱导人血单核部分（淋巴细胞）中多药耐药1（MDR 1）和药物代谢细胞色素P450（P450）基因mRNA表达的能力。共有50名健康志愿者（年龄，18-74岁）参加了两项研究，其中600 mg利福平口服给药，每天晚上一次，持续7天。其中20例患者在利福平给药前后也接受了非索非那定治疗。基线时，MDR 1和CYP 2C 8 mRNA分别在100%（50/50）和95%（35/37）的个体中表达。基线时雄性和雌性之间MDR 1 mRNA表达存在显著差异（P 0.05）。有趣的是，58%的个体（n = 29）显示MDR 1 mRNA表达增加120%[95%置信区间（CI）; 120%;范围，81-153%;应答者]。相比之下，其余42%的个体（n = 21）表现出平均降低-5.2%（95% CI; -5.2%;范围：-15至+4%;无应答者）。应答者和无应答者的利福平稳态血清谷浓度无显著差异（P > 0.05）。同样，在20名志愿者中观察到的淋巴细胞中MDR 1 mRNA表达诱导与观察到的非索非那定口服清除率增加之间也无相关性。在基线和利福平治疗后，CYP 2 E1、CYP 3A 5、CYP 3A 7、CYP 4A 11和CYP 4 B1基因的mRNA均不表达。相比之下，利福平给药前后淋巴细胞中均检测不到CYP 2C 9和CYP 3A 4 mRNA。人淋巴细胞中MDR 1和P450 mRNA的基线表达和诱导的个体间差异似乎很大，可能不能反映这些酶在其他组织中的表达。
Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative, competitive RT-PCR were used to examine the capability of rifampin to induce the expression of mRNA derived from multidrug resistance-1 (MDR1) and drug-metabolizing cytochrome P450 (P450) genes in the mononuclear fraction (lymphocytes) of human blood. A total of 50 healthy volunteers (age, 18-74) participated in two studies in which 600 mg of rifampin was administered orally once daily in the evening for 7 days. Twenty of these individuals also received fexofenadine before and after rifampin dosing. MDR1 and CYP2C8 mRNAs were expressed in 100% (50 of 50) and 95% (35 of 37) of individuals, respectively, at baseline. A significant (P 0.05) difference in MDR1 mRNA expression between males and females at baseline. Interestingly, 58% of the individuals (n = 29) demonstrated a 120% increase [95% confidence interval (CI); 120%; range, 81-153%; responders] in MDR1 mRNA expression. In contrast, the remaining 42% of individuals (n = 21) exhibited a mean decrease of -5.2% (95% CI; -5.2%; range, -15 to +4%; nonresponders). Rifampin steady-state trough serum concentrations were not significantly different (P > 0.05) between responders and nonresponders. Likewise, there was no relationship between the observed induction in MDR1 mRNA expression in lymphocytes and the observed increase in fexofenadine oral clearance in twenty volunteers. The mRNA of CYP2E1, CYP3A5, CYP3A7, CYP4A11, and CYP4B1 genes were variably expressed at baseline and following rifampin treatment. In contrast, CYP2C9 and CYP3A4 mRNAs were undetectable in lymphocytes both before and after rifampin dosing. Interindividual variability in baseline expression and inducibility of MDR1 and P450 mRNA in human lymphocytes appeared to be substantial and may not reflect the expression of these enzymes in other tissues.