Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers.
Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers.
复制标题
细胞色素 P450 3A 诱导剂对雄性和雌性大鼠肝脏中 P-糖蛋白表达的调节。
DOI：
10.1016/s0006-2952(97)00436-x
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发表时间：
1998
影响因子：
5.8
通讯作者：
Benet,LZ
中科院分区：
文献类型：
--
作者：
Salphati,L;Benet,LZ
据报道，P-糖蛋白（Pgp）和细胞色素P450 3A（CYP 3A）底物和调节剂之间存在很强的重叠。为了验证CYP 3A和Pgp协同调节的假设，我们检测了已知的CYP 3A诱导剂（三乙酰竹桃霉素、利福平、地塞米松、双烯醇酮16α-甲腈）对大鼠肝脏Pgp表达的影响。我们还研究了性别特异性表达的Pgp，并比较其对地塞米松的反应，雄性和雌性大鼠之间。在雄性大鼠中，蛋白质印迹分析显示利福平和地塞米松分别导致Pgp水平增加50%和5倍。使用三种Pgp亚型的基因特异性探针进行的RNA酶保护测定显示，地塞米松给药后mdr 2 mRNA水平增加了3倍，利福平治疗后增加了2倍。三乙酰竹桃霉素和双烯醇酮16α-甲腈对Pgp表达和mRNA水平无影响。我们还观察到，Pgp的基础水平是40%，男性大鼠比女性和mdr 2 mRNA水平的一半，在男性大鼠的女性。与雄性大鼠的结果相反，地塞米松使雌性大鼠的Pgp表达降低约60%，并使mdr 2 mRNA水平降低30%。在雌性或雄性大鼠中未检测到mdr 1a和mdr 1b。我们的结论是，在使用的剂量方案，CYP 3A和Pgp的CYP 3A诱导剂的反应是独立调节大鼠肝脏。此外，本研究表明Pgp的表达和调节具有性别特异性。
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 16α-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 16α-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.