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

内分泌干扰化学物质对宿主防御机制（转运蛋白、酶）的影响

基本信息

批准号：
11557200
负责人：
MURAKAMI Teruo
金额：
$ 8.32万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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.

ATP依赖性外排泵P-糖蛋白（P-GP）具有重要且主要的作用，以及在宿主防御机制中的各种酶。在酶中，细胞色素P450（CYP）3a尤其重要，因为临床上可用药物中50％以上的药物是CYP3A的底物。蛋白质都限制了涌入（吸收）并促进其底物的外排（消除），以防止其在包括肠，肝，肾脏，眼睛和脑在内的组织中积累。在本研究中，我们评估了内分泌破坏化学物质（ECD）对体外P-gp/GYP3A的影响（表达P-gp）和体内（大鼠）。染料木黄酮以及标准雌激素（如雌二醇孕酮和甲醇）显着抑制了P-gp的功能。同样，在CACO-2细胞中，发现染料木黄酮的转运是由p-gp介导的。（2）雌二醇和他莫昔芬（雌激素受体的拮抗剂）的纳负暴露降低了两者中8周大时的性器官体重（3）在8周大的肝P-PG和CYP3A活动中发现了显着的性别差异：CYP3A，男性>女性； P-gp，女性>雄性。（4）雌二醇的纳纳那变性增加了CYP3A活性，尤其是在雌性大鼠中。（5）他莫莫昔芬的Naonatal暴露在雌性大鼠中增加了P-gp的功能和表达。这些结果表明，这些结果表明ECD的暴露，尤其是在新生儿时期，会影响女性尤其极大地影响宿主的扩散机制。因此，P-gp/CYP3A底物的药代动力学和药效学将在内分泌系统改变的人类受试者中调节。