Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver.
OBJECTIVE
The aim of the study was to determine whether a correlation exists between MDR1 (ABCB1) gene polymorphisms at positions 3435 (C3435T) and 2677 (G2677T(A)) and the expression of human hepatic P-glycoprotein (P-gp).


METHODS
P-gp protein expression in 26 human livers was assessed by Western blotting and ABCB1 mRNA expression was determined by real time RT-PCR. The C3435T and G2677T(A) polymorphisms were identified by RFLP and direct sequence analysis, respectively.


RESULTS
The C and G allele frequencies for the C3435T and G2677T(A) polymorphisms were 0.48 and 0.79, respectively, and the genotypes were in Hardy-Weinberg equilibrium. There was a 200- and 20-fold variation in the expression of ABCB1 mRNA and Pgp protein expression, respectively. There were no differences in mRNA and protein expression identified amongst the different genotypes attributable to the C3435T and G2677T(A) polymorphisms in the ABCB1 gene. Exposure to a PXR ligand prior to death did not influence mRNA or protein expression.


CONCLUSIONS
There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in the ABCB1 gene, although our study is limited by a small sample size.
Owen
Andrew
A
Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool, L69 3GE, U.K.
Goldring
Chris
C
Morgan
Paul
P
Chadwick
David
D
Park
B Kevin
BK
Pirmohamed
Munir
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger