A new study of enzyme induction involved in pharmacokinetic : Identification of molecular mechanism for a novel enzyme induction

涉及药代动力学的酶诱导的新研究：鉴定新型酶诱导的分子机制

• 批准号: 21590173
• 负责人: NAGATA Kiyoshi
• 金额: $ 3.08万
• 依托单位: Tohoku Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590173/
• 关键词: MRP3; 酵素誘導; 転写因子; 核内レセプター; CYP3A4; レポーター; シス-エレメント; エンハンサー

Drug metabolizing enzyme CYP3A4 and excretory transporter MRP3 are induced by same compounds, being predicted the existence of similar molecular mechanism in both induction. CYP3A4 and MRP3 were strongly induced by treatment with clotrimazole and aryl hydrocarbon receptor(AhR) ligands such as polycyclic aromatic hydrocarbons. Those compounds induced CYP3A4 through activation of pregnane X receptor(PXR) but not through activation of AhR. On the other hand, MRP3 induction was not involved in AhR activation, although a region including a nucleotide sequence similar to AhR binding cis-element was found in an enhancer region(-6.8Kb). Together with these results, CYP3A4 is predominantly induced through activation of PXR and MRP3 seems to be induced through a novel gene transcription involving no receptor previously reported.

药物代谢酶CYP3A4和排泄转运蛋白MRP3被相同的化合物诱导，预测两者的诱导存在相似的分子机制。氯霉唑和芳烃受体（AhR）配体如多环芳烃对CYP3A4和MRP3有强烈的诱导作用。这些化合物通过激活妊娠X受体（PXR）而不是通过激活AhR诱导CYP3A4。另一方面，MRP3的诱导不参与AhR的激活，尽管在增强子区（-6.8Kb）发现了一个包含与AhR结合顺式元件相似的核苷酸序列的区域。结合这些结果，CYP3A4主要是通过PXR的激活诱导的，而MRP3似乎是通过一种新的基因转录诱导的，该基因转录不涉及先前报道的受体。

项目成果

Tamihide Matsunaga : Effect of quercetin on differentiation into hepatocyte-like cells from human induced pluripotent stem cells

Tamihide Matsunaga : 槲皮素对人诱导多能干细胞分化为肝细胞样细胞的影响

• 发表时间: 2011
• 作者: Yuki Kondo;Takahiro Iwao;Masayoshi Saito;Takuro Niwa;Koichi Kurose;Kiyoshi Nagata
• 通讯作者: Kiyoshi Nagata

Hepatocyte nuclear factor-6 enhances expression of CYP3A4 in HepG2 cells and hepatooyte-like cells differentiated from human induced pluripotent stem cells

肝细胞核因子6增强人诱导多能干细胞分化的HepG2细胞和肝细胞样细胞中CYP3A4的表达

• 发表时间: 2011
• 作者: Sasaki T;Tanaka Y;Takahashi S;Kumagai T;Sakaguchi S;Matsunaga T;Nagata K
• 通讯作者: Nagata K

CYP3A4転写活性に影響を与えるFBS中誠分の同定

影响 CYP3A4 转录活性的 FBS 成分的鉴定

• 发表时间: 2010
• 作者: 福士素子;熊谷健;佐々木崇光;永田清
• 通讯作者: 永田清

アテノウイルスベクターを用いた薬物代謝・毒性評価系の確立

利用慢病毒载体建立药物代谢/毒性评价体系

• 发表时间: 2009
• 作者: Norie Murayama;Kanako Yajima;Makiko Shimizu;Masahiro Utoh;Hiroshi Yamazaki;高橋昌悟
• 通讯作者: 高橋昌悟

MRP3における新規転写誘導機構の解明

阐明 MRP3 中的新型转录诱导机制

• 发表时间: 2010
• 作者: T Sasaki;M Horikawa;K Orikasa;M Sato;Y Arai;Y Mitachi;M Mizugaki;M Ishikawa;M Hiratsuka;Kanako Sakuyama;Takamitsu Sasaki;Shuta Uiiie;福士素子;沼田喜弘
• 通讯作者: 沼田喜弘