Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver.
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.
Meier
Yvonne
Y
Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland.
Pauli-Magnus
Christiane
C
Zanger
Ulrich M
UM
Klein
Kathrin
K
Schaeffeler
Elke
E
Nussler
Andreas K
AK
Nussler
Natascha
N
Eichelbaum
Michel
M
Meier
Peter J
PJ
Stieger
Bruno
B
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001648:Bile Canaliculi / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002780:Cholestasis, Intrahepatic / Q000378:metabolism / Q000601:surgery; D004247:DNA / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012737:Sex Factors
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D000089762:Multidrug Resistance-Associated Protein 2; D004247:DNA