Effect of endocrine disrupting chemicals on host defense mechanism (transpoter, enzymes)

atp依赖性外排泵p -糖蛋白（P-gp）与多种酶一起在宿主防御机制中发挥重要作用。在酶中，细胞色素P450 (CYP)3A尤为重要，因为临床可用药物中超过50%的药物是CYP3A的底物。这两种蛋白质限制其底物的流入（吸收）并促进其流出（消除），以防止其在组织中积聚，包括肠、肝、肾、眼和脑。在本研究中，我们在体外（表达P-gp的细胞）和体内（大鼠）评估了内分泌干扰化学物质（ECDs）对P-gp/GYP3A的影响。(1)细胞内双酚a、三丁基锡、染料木素以及雌二醇、孕酮、己甾醇等标准雌激素均显著抑制P-gp功能。此外，在Caco-2细胞中，染料木素的转运被发现是由P-gp介导的。(2)雌二醇和他莫昔芬（雌激素受体拮抗剂）在8周龄时对雄性和雌性大鼠的性器官重量均有降低。(3) 8周龄时肝脏P-pg和CYP3A活性存在显著的性别差异：CYP3A，雄性比雌性多；P-gp，女性>，男性。(4)母体暴露于雌二醇会增加CYP3A活性，尤其是雌性大鼠。(5)雌性大鼠在出生时暴露于他莫昔芬会增加P-gp的功能和表达。这些结果表明，暴露于ECDs，特别是在新生儿期，对宿主差异机制影响很大，尤其是雌性。因此，P-gp/CYP3A底物的药代动力学和药效学将在这些内分泌系统改变的人类受试者中被调节。

ATP-dependent efflux pump, P-glycoprotein (P-gp), has an important and major role, as well as various enzymes in host defense mechanisms. Among enzymes, cytochrome P450 (CYP)3A is particularly important, because drugs of more than 50 % among clinically available drugs are substrates of CYP3A. Both proteins limit the influx (absorption) and facilitate the efflux (elimination) of their substrates, to prevent their accumulation in tissues including intestine, liver, kidney, eye and brain. In the present study, we evaluate the effect of endocrine disrupting chemicals (ECDs) on P-gp/GYP3A in vitro (cells expressing P-gp) and in vivo (rats).(1) In cells, bisphenol-A, tributyltin and genistein, as well as standard estrogens such as estradiol progesterone and hexesterol suppressed the P-gp function significantly. Also, in Caco-2 cells, the transport of genistein was found to be mediated by P-gp.(2) The naonatal exposure of estradiol and tamoxifen (an antagonist of estrogen receptor) decreased the sexal organ weights at 8 weeks old in both male and female rats.(3) A significant sex difference was found in hepatic P-pg and CYP3A activities at 8 weeks old : CYP3A, male > female ; P-gp, Female > male.(4) The naonatal exposure of estradiol increased CYP3A activity, especially in female rats.(5) The naonatal exposure of tamoxifen increased P-gp function and expression, in female rats.These results indicate that the exposure of ECDs, especially at neonatal period, affect host diffence mechanism of particularly female greatly. Thus, the pharmacokinetics and pharmacodynamics of P-gp/CYP3A substrates would be modulated in such human subjects with altered endocrine systems.