Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver
Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver
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DOI：
10.1124/mol.105.011080
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发表时间：
2005-05-01
影响因子：
3.6
通讯作者：
Schinkel, AH
中科院分区：
文献类型：
--
作者：
Merino, G;van Herwaarden, AE;Schinkel, AH
乳腺癌耐药蛋白 (BCRP/ABCG2) 是一种 ATP 结合盒药物外排转运蛋白，存在于肝脏和其他组织中，影响许多化合物的药理行为。为了评估 BCRP 在性别依赖性药代动力学中的可能作用，我们研究了雄性和雌性野生型和 Bcrp1 敲除小鼠中几种鼠 Bcrp1 底物的体内分布。口服抗生素呋喃妥因后，野生型雌性小鼠的血浆浓度-时间曲线下面积比野生型雄性小鼠高约2倍。此外，静脉注射后。给予呋喃妥因、抗溃疡药西咪替丁、抗癌药托泊替康和致癌物2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶(PhIP)后，野生型雌性小鼠的血浆水平均显着高于野生型雄性小鼠。对小鼠 Bcrp1 在几个药代动力学重要组织中表达的分析表明，与雌性小鼠相比，雄性小鼠中仅肝脏 Bcrp1 表达较高。与这种差异一致，雄性野生型小鼠中呋喃妥因和 PhIP 的肝胆排泄量分别是雌性野生型小鼠的 9 倍和约 2 倍。在 Bcrp1(-/-) 小鼠中，任何测试化合物的血浆水平或肝胆排泄均未观察到显着的性别差异，表明 Bcrp1 是野生型小鼠中性别差异的主要原因。对人类 BCRP 肝脏表达的分析也表明，与女性相比，男性的表达更高。总之，肝脏中 BCRP/Bcrp1 的性别依赖性表达可能是 BCRP 底物药代动力学性别特异性变异的原因，对药物的临床治疗应用和毒性风险具有潜在影响。
The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter present in the liver and other tissues that affects the pharmacological behavior of many compounds. To assess the possible role of BCRP in sex-dependent pharmacokinetics, we studied the in vivo disposition of several murine Bcrp1 substrates in male and female wild-type and Bcrp1 knockout mice. After oral administration of the antibiotic nitrofurantoin, the area under the plasma concentrationtime curve in wild-type female mice was approximately 2-fold higher than in wild-type male mice. Moreover, after i.v. administration of nitrofurantoin, the antiulcerative cimetidine, the anticancer drug topotecan, and the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the plasma levels in wild-type female mice were all significantly higher than those in wild- type male mice. Analysis of the expression of murine Bcrp1 in several pharmacokinetically important tissues showed that only the hepatic Bcrp1 expression was higher in male mice compared with female mice. In line with this difference, the hepatobiliary excretion for nitrofurantoin and PhIP was, respectively, 9-fold higher and approximately 2-fold higher in male compared with female wild-type mice. No significant sex differences were observed in plasma levels or hepatobiliary excretion for any of the tested compounds in Bcrp1(-/-) mice, indicating that Bcrp1 was the main cause of the sex difference in wild-type mice. Analysis of hepatic expression of human BCRP also indicated a higher expression in men compared with women. In conclusion, sex-dependent expression of BCRP/Bcrp1 in the liver may be a cause of sex-specific variability in the pharmacokinetics of BCRP substrates, with potential impact on the clinical-therapeutic applications and toxicity risks of drugs.