ABCMdb

PMID: 19949922

Cascorbi I, Haenisch S
Pharmacogenetics of ATP-binding cassette transporters and clinical implications.
Methods Mol Biol. 2010;596:95-121., [PubMed]

Sentences

No. Mutations Sentence Comment

52 ABCC1 p.Ala893Ser ABCB1 p.Asn183Ser ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp ABCB1 p.Gln1107Pro ABCB1 p.Gln1107Pro ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Arg492Cys ABCB1 p.Arg492Cys ABCB1 p.Met986Val ABCB1 p.Met986Val Functional Significance of ABCB1 SNPs Table6.3 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies (134) Position Amino acid or effect Frequency of the variant allele 5'-Flanking -2903 T>C 0.02a 5'-Flanking -2410 T>C 0.10a 5'-Flanking -2352 G>A 0.28a 5'-Flanking -1910 T>C 0.10a 5'-Flanking -1717 T>C 0.02a 5'-Flanking -1325 A>G 0.02a 5'-Flanking -934 A>G 0.10a 5'-Flanking -692 T>C 0.10a 5'-Flanking -41 A>G 0.09b IVS 1a -145 C>G 0.02b IVS 1b -129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 -1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 -35 G>C Intronic 0.006c IVS 5 -25 G>T Intronic 0.16c IVS 6 +139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T Synonymous 0.41d IVS 12 +44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 -76 T>A Intronic 0.46d IVS 17 +137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d c. 4030 Synonymous 0.005b c. 4036 Synonymous 0.30b References: a [42], b [26], c [25], d [28], e [23] with lower activity or expression in Caucasians. Login to comment 59 ABCC1 p.Ala893Ser The missense variant 2677G>T/A coding for the three different amino acids A893S/T exhibits altered transport properties in membrane vesicles from Sf9 insect cells, overexpressing human ABCB1. Login to comment 62 ABCB1 p.Ser400Asn A further rare missense SNP 1199 G>T (frequency 0.05 in Caucasians, (28)) leading to a Ser400Asn amino acid replacement is associated with lower activity and accordingly higher sensitivity against anticancer drugs. Login to comment 76 ABCC1 p.Ala893Ser ABCB1 p.Ser400Asn ABCB1 p.Ser400Asn ABCB1 p.Gly191Arg ABCB1 p.Gly191Arg Table6.4 Functional significance of ABCB1 genetic variants and relevance for clinical outcome Position Amino acid exchange Effect of variant 5'-Flanking -2410 T>C Decreased mRNAa 5'-Flanking -692 T>C Decreased mRNAa c. 571 G>A G191R Reduced chemotherapy resistanceb c. 1199 G>A S400N Elevated activityc c. 1236 C>T Synonymous Increased imatinib disposition and therapy responsed c. 2677 G>T/A A893S/T In vitro increased vmax ,q no effect on vincristine,e increased imatinib response in CMLd c. 3435 C>T Synonymous Decreased mRNA and protein expression,f, g decreased invitro transport,h no effect on expression and bioavailability of talinolol,i no effect on invitro transport,j, k decreased digoxin bioavailability,l increased etoposid disposition,m no effect on AML or ALL outcome,k better prognosis of multiple myeloma,n better chemotherapy response in breast cancer,o no effect in colon cancerp References: a [42], b [69], c [38], d [53], e [51], f [23], g [64], h [31], i [39], j [135], k [65-67], l [40, 41], m [52], n [68], o [74], p [70, 71], q [36] As mentioned earlier, the first systematic study on ABCB1 genetic variability and its association to expression and bioavailability was the first one, showing an association of 3435C>T with digoxin plasma levels. Login to comment 118 ABCB1 p.Gly191Arg In a recent study, a novel ABCB1 571G>A missense variant detected in 6.4% of leukemia patients was reported, causing a Gly191Arg amino acid change (69). Login to comment 134 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Cys1047Ser ABCC1 p.Arg633Gln ABCC1 p.Arg230Gln ABCC1 p.Ala989Thr ABCC1 p.Ser92Phe A thorough investigation on the functional significance of ten nonsynonymous SNPs, leading to amino acid changes C43S, T73I, S92F, T117; R230Q, R633Q, R723Q, A989T, C1047S. Login to comment 135 ABCC1 p.Arg1058Gln ABCC1 p.Ser1512Leu R1058Q, and S1512L was performed by Létourneau et al. Login to comment 139 ABCC1 p.Ala989Thr Lowest capacity was found for A989T, caused by a 2965G>A variant. Login to comment 146 ABCC1 p.Gly671Val In a study on genetic determinants of anthracycline-induced cardiomyopathy in non-Hodgkin lymphoma patients, the ABCC1 Gly671Val variant as well as a haplotype of ABCC2 turned out to be significant risk factors. Login to comment 155 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.Val353Met ABCC1 p.Ala989Thr ABCC1 p.Ser1512Leu ABCC1 p.Ser92Phe ABCC1 p.Arg230Asn ABCC2 (Multidrug Resistance-Associated Protein 2) Table 6.5 Frequency of ABCC1 genetic variants in different populations, position on DNA, putative effect, and frequencies (according to (33, 77-80, 136)) Position Amino acid or effect Orientals Caucasians Function c.128G>C C43S 0.01 - Elevateda c. 218C>T T73I 0.00-0.04 - c. 257C>T S92F 0.00 0.00 Decreaseda c. 350C>T T117M - 0.02 (Decreased)a c. 689G>A R230N 0.00 0.00 (Decreased)a c. 816G>A Synonymous - 0.04 c. 825T>C Synonymous - 0.30 c. 1057G>A V353M 0.00 0.005 Elevateda c. 1299G>T R433S - 0.01 Elevated vmax of doxorubicin, decreased transport of LTC4 a,b c. 1684T>C Synonymous - 0.80 c. 1898G>A R633Q - 0.01 (Decreased)a c. 2012G>T G671V - 0.03 Doxorubicine-induced cardiomyopathyc c. 2168G>A R723Q 0.01-0.07 - Decreaseda c. 2965G>A A989T 0.00 0.005 (Decreased)a c. 3140G>C C1047S 0.00 0.00 c. 3173G>A R1058Q 0.01 - c. 4002G>A Synonymous - 0.28 c. 4535C>T S1512L - 0.03 Decreaseda References: a [81], b [77], c [84] an inducible expression of ABCC2, which contributes also to the phenomenon of drug resistance. Login to comment 190 ABCC2 p.Arg768Trp ABCC2 p.Val417Ile ABCC2 p.Cys1515Tyr ABCC2 p.Ser789Phe ABCC2 p.Val1188Glu ABCC2 p.Ala1450Thr ABCC2 p.Arg1174His ABCC2 p.Asn1244Lys ABCC2 p.Thr486Ile ABCC2 p.Gln1019His ABCC2 p.Ser1367Cys ABCC2 p.Asp883Asn ABCC2 p.Lys961Arg ABCC2 p.Arg100Gln ABCC2 p.Pro19Leu ABCC2 p.Ser281Asn 0.01* (0.00) c. 56 C>T P19L 0.01* c. 234 A>G Synonymous 0.01* c. 299 G>A R100Q 0.01* c. 842 G>A S281N 0.01* c. 1249 G>A V417I 0.13 (0.21) c. 1446 C>G (0.01) c. 1457 C>T T486I 0.03* (0.00) c. 2302 C>T R768W 0.01 (0.00) c. 2366 C>T S789F 0.01 (0.00) c. 2647 G>A D883N 0.01* c. 2882 A>G K961R 0.01* c. 2934 G>A Synonymous 0.05* c. 3039 C>T Synonymous 0.01* c. 3057 G>T Q1019H 0.01* c. 3321 G>T Synonymous 0.01* c. 3521 G>A R1174H 0.01* c. 3542 G>T (0.001) c. 3561 G>A (0.00) c. 3563 T>A V1188E 0.01* (0.05) c. 3732 C>T N1244K 0.01* c. 3972 C>T Synonymous 0.22* (0.34) c. 4100 C>G S1367C 0.01* c. 4290 G>T Synonymous 0.01* c. 4348 G>A A1450T 0.01 (0.00) c. 4488 C>T Synonymous 0.01* c. 4544 G>A C1515Y 0.01* (0.04) association to cholestatic or mixed type hepatitis whereas -24T carriers exhibited more often hepatocellular-type hepatitis after intake of drugs or herbal remedies (96). Login to comment 192 ABCC2 p.Val417Ile A missense SNP 1249G>A (Val417Ile) is located in substrate-binding region of the first transmembrane domain and is associated with lower oral bioavailability and increased residual clearance after intravenous administration of the beta-blocker talinolol, indicating a higher activity of the intestinal transporter (92). Login to comment 210 ABCC2 p.Val417Ile Function and Substrate Specificity Table 6.7 ABCC2 polymorphisms currently described to exhibit a clinical influence ABCC2 polymorphism Effect Clinical impact on Function Reference -1774 G /del 5'-flanking Hepatotoxicity of herbal and conventional drugs Decreased [96] -24C>T 5'-UTR Hepatotoxicity of drugs e.g. diclofenac and herbal remedies Decreased [96, 97] Oral clearance of Mycophenolic acid Decreased [93, 94] Risk of renal failure, renal expression Decreased [90, 95] Bioavailability and side effects of methotrexate Decreased [104] Tumor response and side effects of irinotecan Decreased [105, 106] c.1249G>A V417I Intestinal activity, bioavailability of talinolol Increased [92] Gastrointestinal toxicity of methotrexate Increased? Login to comment 212 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu [98] c.1446C>G T482T Bioavailability of pravastatin Increased [101] c.3563T>A V1188E Higher protein expression in liver Increased [102] c.3972C>T I1324I Intrahepatic cholestasis in pregnancy Decreased [103] c.4544G>A C1515Y Higher protein expression in liver Increased [102] composed of 655 amino acids (109). Login to comment 224 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment 231 ABCG2 p.Gln141Lys ABCG2 p.Val12Asn HEK-293 cells, transfected with wild-type or V12N, ABCG2 showed apical staining with an ABCG2 antibody, but high intracellular staining in case of Q141K, suggesting impaired membrane trafficking or incorrect membrane insertion. Login to comment 232 ABCG2 p.Val12Met Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (119). Login to comment 239 ABCG2 p.Val12Met 0.235 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2 +16 A>G ? Login to comment 242 ABCG2 p.Gln141Lys ABCG2 p.Gln126* ABCG2 p.Gln126* 0.005 c. 376 C>T Q126stop 0.01 0.00a 0.00b Lack of function c. 421 C>A Q141K 0.35 0.11a 0.02b Reduced activity [120, 124, 137] IVS 5 -16 A>G ? Login to comment 244 ABCG2 p.Ser441Asn 0.015 c. 1322 G>A S441N 0.005 c. 1367 A>G ? Login to comment 245 ABCG2 p.Phe489Leu 0.165 c. 1465 A>G F489L 0.005 c.1492 G>C ? Login to comment 253 ABCG2 p.Val12Asn ABCG2 V12N protein was found to be accumulated intracellulary (120) and always apical expression was observed by Kondo et al. Login to comment 258 ABCG2 p.Val12Met Interestingly, V12M was associated with elevated activity compared to the wild-type, whereas ABCG2 with premature stop-codon lacked any activity as expected (37). Login to comment