Interindividual variability of canalicular ATP-binding-cassette (ABC)–transporter expression in human liver

Abstract

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. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html). (HEPATOLOGY 2006;44:62-74.)

No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

“…Therefore, individuals with the 1331CC genotype had an ABCB11 expression of 80% compared with those harboring the 1331TT genotype. Our in vitro study reinforced the results of Byrne et al (2009) and Meier et al (2006) and identified decreased protein stability as a cause of reduced protein expression. Although some missense mutations, such as the D482G, enhanced aberrant splicing shown using a minigene system, this SNP (1331T.C) did not alter the pre-mRNA splicing pattern (Byrne et al, 2009).…”

“…In contrast, 444V was expressed to a greater extent than 444A in CHO-K1 cells (Byrne et al, 2009). Meier et al (2006) studied the hepatic expression of ABCB11 protein in 110 individuals undergoing liver resection and demonstrated a trend toward reduced expression in individuals harboring the 1331C-allele (444A) polymorphism compared with those harboring the 1331T-allele (444V). Semiquantitative evaluation revealed a 1.15-fold higher hepatic ABCB11 protein expression level in individuals with the 1331CC genotype and 0.9-fold lower level in those with the 1331TT genotype when compared with those with the 1331TC genotype.…”

“…An in vitro assay using vesicles isolated from Sf9 insect cells expressing ABCB11 revealed that the bile acid transport activity of 444A is equivalent to that of the wild-type protein (444V) (Lang et al, 2007). Conversely, hepatic expression of the ABCB11 protein was slightly but not significantly reduced in individuals harboring the 444A polymorphism (Meier et al, 2006). Therefore, the effects of this SNP on transport activity and protein expression remain unresolved.…”

The bile salt export pump

“…A strong candidate is the genetic background. Recently, the variation of BSEP protein expression levels was studied in 110 healthy liver specimens by Western blotting [63]. BSEP expression levels of these individuals were found to display a unimodal distribution and showed no correlation with, for example, sex or medication.…”

Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function

“…12 Rare ABCC2 variants such as 1446C4G, 3563T4A and 4544G4A were described to be associated with higher mRNA and protein expression in liver, respectively. 13,14 Currently, it is not exactly known how and on which stage genetic variants interfere with the gene expression of ABCC2. Considering the full-length cDNA of ABCC2, we conducted different in vitro approaches to systematically follow the molecular effect of the most common SNPs (À24C4T, 1249G4A and 3972C4T) in Caucasians.…”