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Hepatic and renal expression of organic anion transporters during jaundice, and improvement of transcellular organic anion transport after transfection with Multidrug Resistance-associated Protein 2(MRP2) gene.

黄疸期间肝脏和肾脏有机阴离子转运蛋白的表达，以及转染多药耐药相关蛋白2（MRP2）基因后跨细胞有机阴离子转运的改善。

基本信息

批准号：
14370178
负责人：
ADACHI Yukihiko
金额：
$ 7.68万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Various mutations of bilirubin UDP-glucronosyltransferase gene (UGT1A1) have been reported in patients with familial unconjugated hyperbilirubinemia. To clarify the incidence of this gene mutation in the Japanese population, we investigated the presence of UGT1A1 mutation in a group of Japanese patients with Crigler Najjar syndrome(CNS) type 2 and Gilbert's syndrome(GS), as well as in healthy anicteric subjects. Polymorphisms in the coding region of UGT1A1 were commonly observed in Japanese patients with GS and in healthy subjects. The genetic basis of hyperbilirubinemia appears to be different between the Japanese population and Caucasians. In this study, we additionally identified a novel mutation, heterozygous P364L. The P364L UGT1A1 enzyme activity was 64.4% lower than the wild type enzyme activity.Gunn rat is an animal model of CNS type I. UGT1A1 has been reported to be deficient in CNS type 1. We evaluated expressions of organic anion transporting polypeptide(oatp) 1, oatp2, mult … More idrug resistance-associated protein(mrp) 2, and mrp3 in the liver and kidney of Gunn rats. Decreased expression of oatpl and increased expression of mrp3 were observed in the liver and kidney of Gunn rats.Eisai hyperbilirubinuria rat(EHBR) is an animal model of Dubin-Johnson syndrome that suffers from jaundice due to impaired biliary excretion of bilirubin glucuronides. In EHBR, deficiency of mrp2 causes defective biliary excretion of numerous organic anions. Hepatic and renal expression of mrp3 was significantly higher in EHBR than in SD rats. Hepatic and renal expression of mrp1 and mrp6 mRNA was not significantly different between EHBR and SD rats. Mrp1 and mrp6 proteins were hardly expressed in liver and kidney of both EHBR and SD rats. In contrast to mrp3, hepatic expression of oatp1 and oatp2 mRNA were lower in EHBR than in SD rats. Immunohistochemistry disclosed that hepatic and renal mrp3 protein was localized at the basolateral membrane.We developed a protein expression vector (pDEST_<26>) which includes the full length of human MRP2 cDNA, which is encapsulated by the envelope protein of the hemoagglutinating virus of Japan (HJV). Gene transfection with pDEST_<26> was performed on EHBR. We disclosed that transcellular transport of conjugated bilirubin was recovered in the liver from EHBR after transfection with MRP2. Serum conjugated bilirubin level decreased to normal levels in EHBR (35.7 μmol/L to 6.4 μmol/L) after transfection. Mrp3 expression decreased while Oatp1 or Oatp2 expression increased in the liver from transfected EHBR but these expressions were not significantly different from control SD rats. Less

在家族性非结合型高胆红素血症患者中，胆红素尿苷二磷酸葡萄糖基转移酶基因（UGT 1A 1）有多种突变。为了阐明该基因突变在日本人群中的发生率，我们研究了一组患有Crigler Najjar综合征（CNS）2型和吉尔伯特综合征（GS）的日本患者以及健康无黄疸受试者中UGT 1A 1突变的存在。在日本GS患者和健康受试者中普遍观察到UGT 1A 1编码区的多态性。高胆红素血症的遗传基础在日本人群和白种人之间似乎是不同的。在这项研究中，我们还发现了一个新的突变，杂合子P364 L。P364 L UGT 1A 1酶活性比野生型酶活性低64.4%。古恩大鼠是CNS I型的动物模型。据报道，UGT 1A 1在CNS 1型中存在缺陷。方法：采用免疫组织化学方法检测不同浓度的HLA-D1、HLA-D2、HLA-D3、HLA-D4、HLA-D5、HLA-D 6、HLA-D 7、HLA-D8、HLA-D 7、HLA-D8、HLA-D 7 ...更多信息古恩大鼠肝、肾组织中的耐药相关蛋白（mrp）2和mrp 3。古恩大鼠肝、肾组织中oatpl表达减少，mrp 3表达增加。高胆红素尿大鼠（EHBR）是一种因胆汁中胆红素葡萄糖醛酸苷排泄障碍而导致黄疸的Dubin-Johnson综合征动物模型。在EHBR中，mrp 2的缺乏导致许多有机阴离子的胆汁排泄缺陷。EHBR大鼠肝、肾组织中mrp 3的表达明显高于SD大鼠。肝、肾mrp 1和mrp 6 mRNA表达在EHBR和SD大鼠间无显著差异。Mrp 1和Mrp 6蛋白在EHBR和SD大鼠肝、肾组织中几乎不表达。与mrp 3相比，EHBR大鼠肝脏oatp 1和oatp 2 mRNA的表达较SD大鼠低。免疫组化结果显示，mrp 3蛋白定位于肝、肾的基底膜，我们构建了一个含有人MRP 2全长cDNA的蛋白表达载体（pDEST_<26>），该载体被日本血凝病毒（HJV）的包膜蛋白包裹。用pDEST_<26>转染EHBR。我们发现，MRP 2转染后，结合胆红素的跨细胞转运在EHBR的肝脏中恢复。EHBR转染后血清结合胆红素水平降至正常水平（35.7 μmol/L ~ 6.4 μmol/L）。转染EHBR大鼠肝脏Mrp 3表达降低，Oatp 1和Oatp 2表达升高，但与对照组相比无显著性差异。少

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tanaka Y., Yoshikawa M., Kobayashi Y, Kuroda M, Kaito M, Shiroi A, Yamao J, Fukui H, Ishizuka S, Adachi Y: "Expression of hepatobiliary organic anion transporters and bilirubin-conjugating enzymes in differentiating embryonic stem cells."Biochemical and B

Tanaka Y.、Yoshikawa M.、Kobayashi Y、Kuroda M、Kaito M、Shiroi A、Yamao J、Fukui H、Ishizuka S、Adachi Y：“分化胚胎干细胞中肝胆有机阴离子转运蛋白和胆红素结合酶的表达。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats

DOI：
10.1016/j.hepres.2004.02.008
发表时间：
2004-05-01
期刊：
HEPATOLOGY RESEARCH
影响因子：
4.2
作者：
Higuchi, K;Kobayashi, Y;Adachi, Y
通讯作者：
Adachi, Y

Genetic polymorphism of bilirubin UDP-glucronosyltransferase gene (UGT1A1) in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects.

日本克里格勒-纳贾尔综合征或吉尔伯特综合征患者以及日本健康受试者胆红素 UDP-葡萄糖醛酸基转移酶基因 (UGT1A1) 的遗传多态性。

DOI：
发表时间：
2004
期刊：
J Gastroenterol Hepatol 19
影响因子：
0
作者：
Higuchi K et al.;Tanaka;Toshio Itani;Jun Araki;Rumi Mifuji;Masahiko Kaito;Takeuchi K et al.
通讯作者：
Takeuchi K et al.

小林由直, 足立幸彦: "体質性黄疸"肝臓. 44・10. 483-491 (2003)

小林由直，安达幸彦：“体质性黄疸”肝脏44·10（2003）。