ABCB1 p.Cys431Trp
| Predicted by SNAP2: | A: N (53%), D: D (91%), E: D (91%), F: D (85%), G: D (80%), H: D (91%), I: D (85%), K: D (91%), L: D (85%), M: D (59%), N: D (85%), P: D (91%), Q: D (91%), R: D (91%), S: N (57%), T: D (80%), V: D (80%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] A novel MDR1 GT1292-3TG (Cys431Leu) genetic variat... AAPS J. 2010 Dec;12(4):548-55. Epub 2010 Jul 10. Crouthamel MH, Wu D, Yang Z, Ho RJ
A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions.
AAPS J. 2010 Dec;12(4):548-55. Epub 2010 Jul 10., [PMID:20623213]
Abstract [show]
P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood-brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 (GT1292-3TG) (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 (GT1292-3TG) recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 (GT1292-3TG) recombinant cells exposed exhibited a 75% decrease in IC for doxorubicin (162.6 +/- 17.4 to 37.9 +/- 2.6 nM) and a 50% decrease in IC(50) for paclitaxel (155.7 +/- 27.5 to 87.7 +/- 9.2 nM), vinblastine (128.0 +/- 15.9 to 65.9 +/- 5.1 nM), and vincristine (593.7 +/- 61.8 to 307.3 +/- 17.0 nM). The effects of the Cys431Leu variation, due to MDR1 (GT1292-3TG) nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p < 0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p < 0.05). Collectively, these data suggest MDR1 (GT1292-3TG) variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype.
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No. Sentence Comment
220 If these mutations were to occur independently of one another, they would result in a Cys431Phe transition (G1292T) or Cys431Trp transition (T1293G).
X
ABCB1 p.Cys431Trp 20623213:220:119
status: NEW222 Regardless, if our hypothesis is correct in that the change in P-gp-mediated resistance and uptake is due to the increase in size and hydrophobicity of the resulting amino acid 431 compared with Cys, we believe that the Cys431Phe and Cys431Trp may have similar results to the Cys431Leu transition, and remains to be investigated.
X
ABCB1 p.Cys431Trp 20623213:222:234
status: NEW