Salphati L, Benet L Z
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Biochem Pharmacol. 1998 Feb 15;55(4):387-95. doi: 10.1016/s0006-2952(97)00436-x.
A strong overlap between P-glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) substrates and modulators has been reported. To test the hypothesis that CYP3A and Pgp are coordinately regulated, we examined the effects of known inducers of CYP3A (triacetyloleandomycin, rifampicin, dexamethasone, pregnenolone 16alpha-carbonitrile) on Pgp expression in rat liver. We also investigated the gender-specific expression of Pgp and compared its response to dexamethasone between male and female rats. In male rats, western blot analyses showed that rifampicin and dexamethasone caused 50% and 5-fold increases in Pgp levels, respectively. RNase protection assays using gene-specific probes for the three Pgp isoforms revealed a 3-fold increase in mdr2 mRNA levels after dexamethasone administration and a 2-fold increase following rifampicin treatment. Triacetyloleandomycin and pregnenolone 16alpha-carbonitrile had no effect on Pgp expression and mRNA levels. We also observed that the basal level of Pgp was 40% lower in male rats than in females and that mdr2 mRNA levels in male rats were one-half those in females. As opposed to the results in male rats, dexamethasone reduced Pgp expression by approximately 60% and caused a 30% decrease in mdr2 mRNA levels in female rats. Mdr1a was not affected and mdr1b was not detected in female or male rats. We conclude that, at the dosage regimen used, CYP3A and Pgp responses to CYP3A inducers are regulated independently in rat liver. In addition, this study shows that Pgp expression and regulation are gender specific.
据报道，P-糖蛋白（Pgp）与细胞色素P450 3A（CYP3A）的底物和调节剂之间存在强烈重叠。为了验证CYP3A和Pgp受到协同调节这一假说，我们研究了已知的CYP3A诱导剂（三乙酰竹桃霉素、利福平、地塞米松、孕烯醇酮16α-腈）对大鼠肝脏中Pgp表达的影响。我们还研究了Pgp的性别特异性表达，并比较了雄性和雌性大鼠对其对CYP3A诱导剂的反应。在雄性大鼠中，蛋白质免疫印迹分析表明，利福平和地塞米松分别使Pgp水平增加了50%和5倍。使用针对三种Pgp亚型的基因特异性探针进行的核糖核酸酶保护试验显示，地塞米松给药后mdr2 mRNA水平增加了3倍，利福平处理后增加了2倍。三乙酰竹桃霉素和孕烯醇酮16α-腈对Pgp表达和mRNA水平没有影响。我们还观察到，雄性大鼠中Pgp的基础水平比雌性大鼠低40%，雄性大鼠中mdr2 mRNA水平是雌性大鼠的一半。与雄性大鼠的结果相反，地塞米松使雌性大鼠的Pgp表达降低了约60%，并使mdr2 mRNA水平降低了30%。雌性或雄性大鼠中的Mdr1a未受影响，未检测到Mdr1b。我们得出结论，在所使用的给药方案下，大鼠肝脏中CYP3A和Pgp对CYP3A诱导剂的反应是独立调节的。此外，本研究表明Pgp的表达和调节具有性别特异性。
