Glutaric aciduria type I and methylmalonic aciduria: Simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus

被引：57

作者：

Sauer, Sven W. ^{[1
]}

Opp, Silvana ^{[1
]}

Mahringer, Anne ^{[3
]}

Kaminski, Marcin M. ^{[2
]}

Thiel, Christian ^{[1
]}

Okun, Juergen G. ^{[1
]}

Fricker, Gert ^{[3
]}

Morath, Marina A. ^{[1
]}

Koelker, Stefan ^{[1
]}

机构：

[1] Univ Childrens Hosp Heidelberg, Dept Gen Pediat, Div Inborn Metab Dis, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Tumor Immunol Program, Div Immunogenet D030, Heidelberg, Germany

[3] Heidelberg Univ, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2010年 / 1802卷 / 06期

关键词：

Glutaric aciduria type I; Methylmalonic aciduria; Dicarboxylic acids; Blood-brain barrier; Organic acid transporter; Plexus choroideus; ORGANIC ANION TRANSPORTERS; COA DEHYDROGENASE; ENCEPHALOPATHIC CRISES; MOUSE MODEL; FAMILY; EFFLUX; NEURODEGENERATION; EXPRESSION; SECONDARY; MEMBRANE;

D O I：

10.1016/j.bbadis.2010.03.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na+-dependent. ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na+-gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na+-dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specific efflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. (C) 2010 Elsevier B.V. All rights reserved.

引用

页码：552 / 560

页数：9