| Co-Investigator(Kenkyū-buntansha) |
NAGAI Junya Hiroshima University, Faculty of Medicene, Assistant Professor, 医学部, 助手 (20301301)
TAKANO Mikihisa Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (20211336)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1999: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Research Abstract |
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.
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