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Ohtsuki, Sumio,Yamaguchi, Hirofumi,Kang, Young-Sook,Hori, Satoko,Terasaki, Tetsuya Pharmaceutical Society of Japan 2010 Biological & pharmaceutical bulletin Vol.33 No.7
<P>The blood–brain barrier (BBB) expresses transporters that influence both dopaminergic neuronal function and drug therapy for Parkinson's disease (PD). The purpose of the present study was to clarify changes of transporter mRNA expression at the BBB in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model of PD, in order to understand the pathophysiological role of BBB transport function in PD. At 7 d after MPTP treatment, mice showed a motor deficit and a loss of dopaminergic neurons. At the same time, L-type amino acid transporter 1 (LAT1) mRNA expression in the brain capillary fraction of the MPTP-treated mice was significantly reduced by 62.6% compared with saline-treated mice, while no significant change was observed in the expression of glucose transporter 1, creatine transporter 1, taurine transporter, organic cation transporter 2, serotonin transporter, norepinephrine transporter and dopamine transporter. LAT1 mRNA expression in whole brain was not affected at 1, 3 and 5 d after the treatment, but was reduced by 46.3% at 7 d. LAT1 mediates the transport of large neutral amino acids, including tyrosine, as well as the PD-therapeutic drug levodopa, across the BBB. Our findings indicate that decreased LAT1 expression at the BBB in PD patients may adversely affect amino acid supply from the circulating blood and levodopa distribution into the brain.</P>
Lee, Na‐,young,Sai, Yoshimichi,Nakashima, Emi,Ohtsuki, Sumio,Kang, Young‐,sook Wiley Subscription Services, Inc., A Wiley Company 2011 journal of pharmaceutical sciences Vol.100 No.9
<P><B>Abstract</B></P><P>Recently, more women were provided with 6‐mercaptopurine (6‐MP) during pregnancy. Therefore, we attempted to clarify the transport mechanisms of 6‐MP through blood–placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR‐TBTs). The uptake of 6‐MP was time‐ and ATP dependent, but sodium independent in TR‐TBTs. 6‐MP was eliminated over 50% from the cells within 30 min. The uptake of 6‐MP was saturable with Michaelis–Menten constant values of 198 μM and 250 μM in TR‐TBT 18d‐1 and TR‐TBT 18d‐2, respectively. 6‐Thioguanine, azathioprine, and hypoxantine, structural analogues of 6‐MP, strongly inhibited [<SUP>14</SUP>C]6‐MP uptake. Equilibrative nucleoside transporter (ENT) inhibitors, adenosine and uridine, significantly inhibited [<SUP>14</SUP>C]6‐MP uptake. However, several organic anions and cations had no effect on [<SUP>14</SUP>C]6‐MP uptake in TR‐TBTs. These results suggest that sodium‐independent transporters, ENTs, may be involved in 6‐MP uptake at the placenta. In addition, multidrug resistance protein (MRP) inhibitors, methotrexate, probenecid, cefmetazole, and sulfinpyrazone, significantly increased the accumulation of [<SUP>14</SUP>C]6‐MP in the cells. It is indicated that 6‐MP may be eliminated across the blood–placental barrier via MRPs. TR‐TBTs expressed mRNA of ENT1, ENT2, MRP4, and MRP5. These findings are important for the therapy of acute lymphoblastic leukemia and autoimmune diseases of pregnant women, and should be useful data in elucidating teratogenicity of 6‐MP during pregnancy. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3773–3782, 2011</P>