ABCMdb

PMID: 16766035

Cascorbi I
Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs.
Pharmacol Ther. 2006 Nov;112(2):457-73., [PubMed]

Sentences

No. Mutations Sentence Comment

706 ABCC1 p.Ala893Ser ABCB1 p.Ala999Thr Mickley et al. (1998) discovered 2 non-synonymous SNP, a 2677G>T transversion in exon 21 and a 2995G>A transition in exon 24 of ABCB1 leading to an A893S and A999T exchanges, respectively. Login to comment 732 ABCC1 p.Ala893Ser Since 3435C>T is linked with 2677G>T/A, leading to an A893S/T amino acid exchange, it was speculated whether this SNP could be causal for P-gp activity. Login to comment 737 ABCC1 p.Ala893Ser Very recently, significantly differences of A893S/T- overexpressing membrane vesicles from Sf9 insect cells for vincristin could be observed. Login to comment 761 ABCC1 p.Ala893Ser ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Gln1107Pro ABCB1 p.Ser1141Thr ABCB1 p.Arg492Cys ABCB1 p.Met986Val 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 0.54e c. 4030 G >C synonymous 0.005b c. 4036 A>G synonymous 0.30b a Taniguchi et al. (2003). Login to comment 821 ABCC1 p.Ala893Ser In essence, further studies on ABCB1 polymorphisms confirmed these associations for 2677G>T/A (Ala893Ser/ Thr) or special ABCB1 haplotype constellations (Brant et al., 2003; Potocnik et al., 2004; Ho et al., 2006). Login to comment 830 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 10 non-synonymous SNP, leading to amino acid changes C43S, T73I, S92F, T117; R230Q, R633Q, R723Q, A989T, C1047S. Login to comment 831 ABCC1 p.Arg1058Gln ABCC1 p.Ser1512Leu R1058Q and S1512L was performed recently by Letourneau et al. (2005) in transfected HEK293T cells. Login to comment 834 ABCC1 p.Ala989Thr Lowest capacity was found for A989T, caused by a 2965G>A variant. Login to comment 840 ABCC1 p.Gly671Val In a recent study on genetic determinants of anthracycline-induced cardiomyopathy in non-hodgkin lymphoma patients, the ABCC1 Gly671Val variant as well as a haplotype of ABCC2 were shown to be significantly associated with acute doxorubicine toxicity. Login to comment 852 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 Table 5 Frequency of ABCC1 genetic variants in different populations, position on DNA, putative effect, and frequencies (according to Le Saux et al., 2000; Ito et al., 2001; Moriya et al., 2002; Conrad et al., 2002; Oselin et al., 2003b; Wang et al., 2004) Position/ Nucleotide Aminoacid or effect Orientals Caucasians Function 128G>C C43S 0.01 - elevateda 218C>T T73I 0.00-0.04 - 257C>T S92F 0.00 0.00 decreaseda 350C>T T117M - 0.02 (decreased)a 689G>A R230N 0.00 0.00 (decreased)a 816G>A synonymous - 0.04 825T>C synonymous - 0.30 1057G>A V353M 0.00 0.005 elevateda 1299G>T R433S - 0.01 elevated Vmax of doxorubicin, decreased transport of LTC4 a,b 1684T>C synonymous - 0.80 1898G>A R633Q - 0.01 (decreased)a 2012G>T G671V - 0.03 doxorubicine-induced cardiomyopathyc 2168G>A R723Q 0.01-0.07 - decreaseda 2965G>A A989T 0.00 0.005 (decreased)a 3140G>C C1047S 0.00 0.00 3173G>A R1058Q 0.01 - 4002G>A synonymous - 0.28 4535C>T S1512L - 0.03 decreaseda a Letourneau et al. (2005). Login to comment 858 ABCC2 p.Val417Ile The most frequent were -24C>T in the 5'-UTR (allele frequency 0.19), 1249G>A (V417I) in exon 10 (frequency 0.12), and a silent 3972C>T SNP in exon 28. Login to comment 859 ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr Other non-synonymous variants such as 2302C>T (A768W) and 2366C>T (S789F) in exon 18, as well as 4348G>A (A1450T) in exon 31, were found with a frequency of about only 1%. Login to comment 867 ABCC2 p.Val417Ile ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr Whereas the transport activity of the wild-type, V417I, and A1450T were similar towards the substrates LTC4, 17β estradiol-D-17β-glucuronide (E217βG), and dinitrophenyl-labeled surfactant protein C (DNP-SP), the transport activity of S789F was slightly higher. Login to comment 868 ABCC2 p.Ala1450Thr However, this variant and A1450T were also located in intracellular compartments and had a lower apical expression. Login to comment 882 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 Exon 2 56 C>T P19L 0.01 Exon 3 234 A>G synonymous 0.01 Exon 3 299 G>A R100Q 0.01 Exon 7 842 G>A S281N 0.01 Exon 10 1249 G>A V417I 0.12 (0.21) Exon 10 1457 C>T T486I 0.03 Exon 18 2302 C>T R768W 0.01 (0.00) Exon 18 2366 C>T S789F 0.01 (0.00) slightly elevated activity, lower expressionb Exon 20 2647 G>A D883N 0.01 Exon 21 2882 A>G K961R 0.01 Exon 22 2934 G>A synonymous 0.05 Exon 22 3039 C>T synonymous 0.01 Exon 22 3057 G>T Q1019H 0.01 Exon 24 3321 G>T synonymous 0.01 Exon 25 3521 G>A R1174H 0.01 Exon 25 3563 T>A V1188E 0.01 Exon 26 3732 C>T N1244K 0.01 Exon 28 3972 C>T synonymous 0.21 (0.34) Exon 29 4100 C>G S1367C 0.01 Exon 30 4290 G>T synonymous 0.01 Exon 31 4348 G>A A1450T 0.01 (0.00) decreased activity, lower expressionb Exon 31 4488 C>T synonymous 0.01 Exon 32 4544 G>A C1515Y 0.01 a Haenisch et al. (in press). Login to comment 885 ABCC2 p.Arg412Gly This patient was heterozygote for a Arg412Gly mutation in the substrate-binding region of ABCC2 (Hulot et al., 2005) (Table 6). Login to comment 901 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment 909 ABCG2 p.Gln141Lys ABCG2 p.Val12Asn 5.3. Association to activity and drug bioavailability 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 914 ABCG2 p.Val12Met 0.235 Exon 2 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2+16 A>G ? Login to comment 917 ABCG2 p.Gln141Lys ABCG2 p.Gln126* ABCG2 p.Gln126* 0.005 Exon 4 c. 376 C>T Q126stop 0.01 Lack of function 0.00a 0.00b Exon 5 c. 421 C>A Q141K 0.35 Reduced activity (Mizuarai et al., 2004; Kobayashi et al., 2005; Sparreboom et al., 2005) 0.11a 0.02b IVS 5-16 A>G ? Login to comment 919 ABCG2 p.Ser441Asn 0.015 Exon 11 c. 1322 G>A S441N 0.005 IVS 11 1367 A>G ? Login to comment 920 ABCG2 p.Phe489Leu 0.165 Exon 12 c. 1465 A>G F489L 0.005 IVS 12 c.1492 G>C ? Login to comment 929 ABCG2 p.Val12Met Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (Morisaki et al., 2005). Login to comment 930 ABCG2 p.Val12Asn In contrast, in a study by Mizuarai et al. (2004) V12N was found to be accumulated intracellulary and apical expression was observed by Kondo et al. (2004). Login to comment 934 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 (Ishikawa et al., 2005). Login to comment