Linked Life Data

15632119

Source:http://linkedlifedata.com/resource/pubmed/id/15632119

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2005-3-7
pubmed:abstractText
Organic anion-transporting polypeptide 1A2 (OATP1A2) is a drug uptake transporter known for broad substrate specificity, including many drugs in clinical use. Therefore, genetic variation in SLCO1A2 may have important implications to the disposition and tissue penetration of substrate drugs. In the present study, we demonstrate OATP1A2 protein expression in human brain capillary and renal distal nephron using immunohistochemistry. We also determined the extent of single nucleotide polymorphisms in SLCO1A2 upon analyses of ethnically defined genomic DNA samples (n = 95 each for African-, Chinese-, European-, and Hispanic-Americans). We identified six nonsynonymous polymorphisms within the coding region of SLCO1A2 (T38C (I13T), A516C (E172D), G559A (A187T), A382T (N128Y), A404T (N135I), and C2003G (T668S)), the allelic frequencies of which appeared to be ethnicity-dependent. In vitro functional assessment revealed that the A516C and A404T variants had markedly reduced capacity for mediating the cellular uptake of OATP1A2 substrates, estrone 3-sulfate and two delta-opioid receptor agonists, deltorphin II, and [D-penicillamine(2,5)]-enkephalin. On the other hand, the G559A and C2003G variants appeared to have substrate-dependent changes in transport activity. Cell surface biotinylation and immunofluorescence confocal microscopy suggested that altered plasma membrane expression of the transporter may contribute to reduced transport activity associated with the A516C, A404T, and C2003G variants. The A404T (N135I) variant also showed a shift in the apparent molecular size, indicative of alterations in glycosylation status. Taken together, these data suggest that SLCO1A2 polymorphisms may be an important yet unrecognized contributor to inter-individual variability in drug disposition and central nervous system entry of substrate drugs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9610-7
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15632119-Amino Acid Sequence, pubmed-meshheading:15632119-Amino Acid Substitution, pubmed-meshheading:15632119-Brain, pubmed-meshheading:15632119-Enkephalin, D-Penicillamine (2,5)-, pubmed-meshheading:15632119-Estrone, pubmed-meshheading:15632119-Humans, pubmed-meshheading:15632119-Kidney, pubmed-meshheading:15632119-Kinetics, pubmed-meshheading:15632119-Liver, pubmed-meshheading:15632119-Models, Molecular, pubmed-meshheading:15632119-Molecular Sequence Data, pubmed-meshheading:15632119-Oligopeptides, pubmed-meshheading:15632119-Organ Specificity, pubmed-meshheading:15632119-Organic Anion Transport Polypeptide C, pubmed-meshheading:15632119-Polymorphism, Genetic, pubmed-meshheading:15632119-Polymorphism, Single Nucleotide, pubmed-meshheading:15632119-Protein Conformation, pubmed-meshheading:15632119-Protein Structure, Secondary
pubmed:year
2005
pubmed:articleTitle
Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry.
pubmed:affiliation
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville Tennessee 37232, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.