人類Multidrug resistance protein（MRP）family 屬於ATP-bindingcassette transporter，MRP 共包含7個成員（MRP1 ~ 7），其中MRP3(ABCC3) 廣泛分部於胃腸道、肝臟、膽管細胞、及腎臟，其功能主要為調節陰離子化合物運送，特別是glucuronide 鍵結化合物。MRP3 之表現量於正常生理狀態下極低，然而於膽汁滯留疾病有所提昇，除此之外，給予實驗用大白鼠cytochrome P450 2B1/2 誘導劑（trans-stilbene oxide、diallyl sulfide、Trans-stilbene oxide、phenobarbital、diallyl sulfide以及oltipraz）可誘導Mrp3基因表現，然而其對MRP3 的調控機轉尚未明確，因此，我們利用大白鼠肝腫瘤細胞株H4IIE，投與TSO，以觀察了解TSO對於Mrp3的調控機轉。於老鼠細胞株H4IIE 給予TSO，以RT-PCR定量mRNA 表現量，發現TSO可呈時間相關性的增加Mrp3mRNA 表現量，於TSO 刺激下，可觀察到JNK、ERK 以及p38 kinase磷酸化增加，投與SP600125 以及U0126，可呈劑量相關性的抑制TSO促進Mrp3 表現量增加，投與SB2038580 則無法抑制TSO 促進Mrp3表現量增加投。與PI3-Kinase 抑制劑- Wortmannin 及LY294002，可呈劑量相關性的抑制TSO 促進Mrp3 表現量增加，然而於TSO 刺激下，AKT 磷酸化程度並無變化。總結上述結果而知，TSO 對於Mrp3 的調控主要透過JNK 及ERK之訊息傳遞，PI3-Kinase可能也參與其中，但並非透過AKT 的活化，p38 kinase之角色則較為不重要。

　　The subfamily C of the ATP-binding cassette transporter superfamily comprises seven members of the multidrug resistance protein (MRP) family (MRP1 ~ 7). MRP3 (ABCC3), a member of the MRP subfamily of transporters is expressed at the basolateral membrane of ileal and colonic enterocytes, hepatocyte, cholangiocytes, and in kidney. Several kinds of organic anions, in particular glucuronide conjugates, are transported via Mrp3. Very little Mrp3 was expressed in liver under normal physiological conditions, and previous studies showed that expression of Mrp3 in rat liver is only detected under various cholestatic conditions. In addition to Cholestasis , Induction of Mrp3 expression in rat liver can occur by treatment with microsomal enzyme inducers that induce cytochrome P450 2B1/2, such as trans-stilbene oxide (TSO), phenobarbital, diallyl sulfide (DAS), oltipraz. However the mechanism for the regulation of Mrp3 is not resolved. The aim of this study was to determine the induction mechanism of Mrp3 expression by TSO.In rat hepatoma H4IIE cells, the Mrp3 expression level was determined by RT-PCR. Mrp3 mRNA expression could be induced by TSO in a dose and time dependent manner. JNK, ERK, and p38 were all activated by TSO. Treatment with SP600125 and U0126 inhibited TSO-inducible Mrp3 mRNA expression. In contrast, treatment with SB203580 didn’t inhibited TSO-inducible Mrp3 mRNA expression. The Mrp3 mRNA could be inhibited by PI3-Kinase inhibitors (Wortmannin and Ly294002). However, Akt didn’t activated by TSO. These results demonstrated that TSO activated JNK and ERK which was responsible for Mrp3 mRNA induction, whereas activation of p38 kinase was not associated with the induction. The TSO-inducible Mrp3 mRNA expression may through PI3-Kinase but not by Akt activation.

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