ABCMdb

PMID: 19950006

Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD
Pharmacogenetics of membrane transporters: an update on current approaches.
Mol Biotechnol. 2010 Feb;44(2):152-67., [PubMed]

Sentences

No. Mutations Sentence Comment

45 ABCC1 p.Ala893Ser There are three single-nucleotide polymorphisms (SNPs) that are common in most ethnic groups and demonstrate strong linkage disequilibrium: the synonymous transition at nucleotide 1236C[T (Gly411Gly) in exon 12, the non-synonymous tri-allelic transition 2677G[T/A (Ala893Ser/ Thr) in exon 21, and the synonymous transition 3435C[T (Ile1145Ile) in exon 26. Login to comment 46 ABCC1 p.Ala893Ser Of these SNPs, only the 2677G[T/ A (Ala893Ser/Thr) transition causes an amino acid change within a structurally important transmembrane domain of the translated protein, and the effects of this transition are controversial and drug-specific [15, 22, 28-30]. Login to comment 57 ABCG2 p.Gln141Lys This SNP results in an amino acid change of Gln to Lys at codon 141 and has been shown in Flp-In-293 cells to have half the protein expression of the wildtype [34]. Login to comment 61 ABCG2 p.Val12Met Another SNP exists at nucleotide 34, resulting in a V12M amino acid change. Login to comment 67 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Arg1058Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Cys1047Ser ABCC1 p.Arg633Gln ABCC1 p.Arg230Gln ABCC1 p.Val353Met ABCC1 p.Ala989Thr ABCC1 p.Ser1512Leu ABCC1 p.Ser92Phe Those studied include C43S, T73I, S92F, T117M, R230Q, V353M, R433S, R633Q, G671V, R723Q, A989T, C1047S, R1058Q, A1337T, and S1512L. Login to comment 69 ABCC1 p.Cys43Ser ABCC1 p.Arg433Ser ABCC1 p.Ala989Thr However, it has been noted that C43S, R433S, and A989T result in decreased ABCB1 function [43]. Login to comment 82 ABCC1 p.Ala893Ser Many of the recent publications regarding transporter genotyping have utilized restriction fragment length polymorphism (RFLP) analysis or direct sequencing, although several other methods of genotyping are available such as resequencing, allele-specific PCR, TaqMan PCR, Fluorescence Resonance Energy Transfer (FRET), etc. Table 2 includes polymerase chain reaction (PCR) and direct Table 2 Primers used to amplify selected polymorphisms in the ABCB1, ABCG2, OATP1B1, and OATP1B3 genes Transporter polymorphism Forward primer Reverse primer Ref. ABCB1 1236C[T PCR amplification 50 -GGCACAAACCAGATAATATTAAGG-30 50 -TATCCTGTCCATCAACACTGACC-30 # Nested PCR 50 -GTTCACTTCAGTTACCCATCTCG-30 50 -TCCTGTCCATCAACACTGACCTG-30 # Sequencing PCR 50 -GTCAGTTCCTATATCCTGTGTCTG-30 50 -TCGCATGGGTCATCTCACCATC-30 # ABCB1 2677G[T/A (A893S/T) PCR amplification 50 -AGGCTATAGGTTCCAGGCTTGC-30 50 -AGAACAGTGTGAAGACAATGGCC-30 # Nested PCR 50 -CCCATCATTCGAATAGCAGGAG-30 50 -GAACAGTGTGAAGACAATGGCCT-30 # Sequencing PCR 50 -ATCCTTCATCTATGGTTGGCAAC-30 50 -TGAGTCCAAGAACTGGCTTTGC-30 # ABCB1 3435C[T PCR amplification 50 -ATCTCACAGTAACTTGGCAGTTTC-30 50 -AACCCAAACAGGAAGTGTGGCC-30 # Sequencing PCR 50 -GCTGGTCCTGAAGTTGATCTGTG-30 50 -AAACAGGAAGTGTGGCCAGATGC-30 # ABCG2 421C[T PCR amplification 50 -TGGCAAATCCTTGTATGAAGCAG-30 50 -TTCACGTACAACACCACATTGCC-30 # Sequencing PCR 50 -GCAGGTTCATCATTAGCTAGAAC-30 50 -CCTACTTATGCTGATCATGAGC-30 # OATP1B1*1b PCR amplification 50 -GCAAATAAAGGGGAATATTTCTC-30 50 -AGAGATGTAATTAAATGTATAC-30 [45] RFLP enzyme ClaI OATP1B1*5 PCR amplification 50 -GTTAAATTTGTAATAGAAATGC-30 50 -GTAGACAAAGGGAAAGTGATCATA-30 [45] Allele specific PCR primers WT 50 -CATACATGTGGATATATGT-30 N/A [45] MT 50 -CATACATGTGGATATATGC-30 D OATP1B3 334T[G (S112A) PCR amplification 50 -CCTTCACAGTTAAATTACATGGTC-30 50 -TATTCATTTCATATAAAACTGTATACC-30 # Sequencing PCR 50 -GGGCATATTTGCATTCATTTGGG-30 50 -CATGATAAATAAAGAAATACATGATG-30 # OATP1B3 699G[A (M233I) PCR amplification 50 -TCCTTGTATTTAGGTAACGTACAG-30 50 -TCAAGTTTGGTTATTTTGGATCAAG-30 # Sequencing PCR 50 -GATCTACCCTTGAAATAATAATGTC-30 50 GTAAAAGCAAAGTATAAATAGGAGC-30 # OATP1B3 1564G[T (G522C) PCR amplification 50 -ATATACAGAATTTCATACACTAATTTC-30 50 -AATTCTAAGAAAATGCATTCTCAAAG-30 # Sequencing PCR 50 -TATTTTGCCTTCACTATTAAGCAAC-30 50 -AATATGAATTTGAGCTCAAAATACAG-30 # Primers are used for direct sequencing following amplification from genomic DNA, unless otherwise indicated # Denotes previously unpublished primer sequencing PCR primers that are currently used in the field to amplify polymorphic regions of DNA. Login to comment 123 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys [70, 71] Docetaxel AUC and overall liver with 3435TT genotype [100-102] Docetaxel is transported by ABCB1 [103] ABCG2 Topotecan Increased accumulation of drug in cells transfected with 421A (Q141K) [104] Increased bioavailability in heterozygous C421A patients [104] Imatinib Increased accumulation of drug in cells transfected with 421A (Q141K) [105] No significant difference in AUC or Cmax in heterozygous C421 patients [105] ABCC1 N/A None to date ABCC2 N/A None to date OATP1B1 Pravastatin Reduced membrane expression of OATP1B1*5 variant [45] Increased AUC in OATP1B1*5 [94, 106] OATP1B3 Leuprolide and goserelin Reduced transport of testosterone with the 334G/699A haplotype [24] Increased progression-free survival in patients with 334G/699A haplotype [97] consequences of the 2677G[T/A polymorphism may be explained by expression alterations alone and not necessarily by altered substrate binding or transport efficiency of the protein. Login to comment