ABCB1 p.Ser400Thr
| ClinVar: |
c.1199G>A
,
p.Ser400Asn
N
, Benign
|
| Predicted by SNAP2: | A: N (87%), C: N (57%), D: N (66%), E: N (78%), F: N (78%), G: N (87%), H: N (97%), I: N (82%), K: N (82%), L: N (72%), M: N (78%), N: N (57%), P: D (91%), Q: N (93%), R: N (97%), T: N (97%), V: N (82%), W: D (85%), Y: N (82%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: D, T: N, V: D, W: D, Y: D, |
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[hide] Substrate-dependent effects of human ABCB1 coding ... J Pharmacol Exp Ther. 2008 May;325(2):435-42. Epub 2008 Feb 20. Gow JM, Hodges LM, Chinn LW, Kroetz DL
Substrate-dependent effects of human ABCB1 coding polymorphisms.
J Pharmacol Exp Ther. 2008 May;325(2):435-42. Epub 2008 Feb 20., [PMID:18287207]
Abstract [show]
One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gp-mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency >/=2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/1236C>T/A893S/3435C>T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner.
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No. Sentence Comment
55 The following variants were created from the reference ABCB1 plasmid in pCIneo: 61AϾG (N21D), 1199GϾA (S400T), 1596TϾG [a nonfunctional nucleotide-binding domain (NBD) mutant], 2005CϾT (R669C), 2677GϾA (A893T), 3421TϾA (S1141T), and 3751GϾA (V1251I).
X
ABCB1 p.Ser400Thr 18287207:55:115
status: NEW103 There are six polymorphic residues that meet these criteria: N21D, S400T, R669C, A893S/T, S1141T, and V1251I.
X
ABCB1 p.Ser400Thr 18287207:103:67
status: NEW111 Intra-and interexperimental replicates (n ϭ 3) for reference, NBD, and variant P-gp samples have TABLE 2 Allele frequencies, evolutionary conservation, and Grantham values for selected ABCB1 nonsynonymous polymorphisms and haplotypes Variant or Haplotype Allele Frequenciesa Amino Acid Conservationc Grantham Valued Nucleotide Change Amino Acid Change AA (n ϭ 200) CA (n ϭ 200) Reference Variant % 61AϾG N21D 2.5 8 23 1199GϾA S400T 1 2.5 d, ha, mk ms, r 46 2005CϾT R669C 1 0 d, ha, mk, r, s 180 2677GϾT A893S 10 46.4 ha, ms, r d, mk, s 99 2677GϾA A893T 0.5 3.6 ha, ms, r 58 3421TϾA S1141T 11.1 0 d, ha, mk, ms, r, s 58 3751GϾA V1251I 0b 0 d, ha, mk, ms, r s 29 1236CϾT/2677GϾT/3435CϾT A893S 6 34 N.A. N.A. N.A. 61AϾG/1236CϾT/2677GϾT/3435CϾT N21D/A893S 2.5 8 N.A. N.A. N.A. N.A., not applicable.
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ABCB1 p.Ser400Thr 18287207:111:456
status: NEW214 There was increased function for A893S and S1141T depending on the substrate, TABLE 3 Substrateand inhibitor-dependent effects of P-gp variants on transport function Variant or Haplotype Calcein-AM BODIPY-FL-Paclitaxel -CsAa ϩCsAb -CsA ϩCsA N21D 1 S400T R669C 1 A893S 1 2 2 A893T 1 2 S1141T 2 V1251I 1 2 2 1236CϾT/A893S/3435CϾT N21D/1236CϾT/A893S/3435CϾT 2 2 a Arrows indicate statistically significant changes in P-gp function relative to reference in the absence of cyclosporin A (-CsA).
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ABCB1 p.Ser400Thr 18287207:214:260
status: NEW