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Interindividual variability of canalicular ATP‐binding‐cassette (ABC)–transporter expression in human liver
Author(s) -
Meier Yvonne,
PauliMagnus Christiane,
Zanger Ulrich M.,
Klein Kathrin,
Schaeffeler Elke,
Nussler Andreas K.,
Nussler Natascha,
Eichelbaum Michel,
Meier Peter J.,
Stieger Bruno
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21214
Subject(s) - multidrug resistance associated protein 2 , biology , atp binding cassette transporter , transporter , bile salt export pump , cholestasis , single nucleotide polymorphism , population , progressive familial intrahepatic cholestasis , medicine , endocrinology , genetics , gene , genotype , environmental health , transplantation , liver transplantation
Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11 ), multidrug resistance protein 3 (MDR3, ABCB4 ), multidrug resistance associated protein 2 (MRP2, ABCC2 ) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes. Hepatic protein expression levels from 110 individuals undergoing liver resection were assessed by Western blot analysis of liver plasma membranes enriched in canalicular marker enzymes. Each individual was genotyped for the following synonymous (s) and nonsynonymous (ns) SNPs: ABCB11: (ns:1457T>C and 2155A>G), ABCB4: (ns:3826A>G) and ABCC2 (ns:1286G>A,3600T>A and 4581G>A) and ABCB1 (ns:2677G>T/A and s:3435C>T). Transporter expression followed unimodal distribution. However, of all tested individuals 30% exhibited a high expression and 32% a low or very low expression phenotype for at least one of the four investigated transport proteins. Transporter expression levels did not correlate with age, sex, underlying liver disease, or presurgery medication. However, low BSEP expression was associated with the 1457C‐allele in ABCB11 ( P = .167) and high MRP2 expression was significantly correlated with the 3600A and 4581A ABCC2 variants ( P = .006). In conclusion , the results demonstrate a considerable interindividual variability of canalicular transporter expression in normal liver. Furthermore, data suggest a polymorphic transporter expression pattern, which might constitute a risk factor for the development of acquired forms of cholestatic liver diseases. (H EPATOLOGY 2006;44:62–74.)