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A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function Fung KL; Gottesman MMBiochim Biophys Acta 2009[May]; 1794 (5): 860-71The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse effect of toxins. The pharmacokinetics of drugs that are also MDR1 substrates also influence disease outcome and treatment efficacy. Although MDR1 is a well-conserved gene, there is increasing evidence that its polymorphisms affect substrate specificity. Three single nucleotide polymorphisms (SNPs) occur frequently and have strong linkage, creating a common haplotype at positions 1236C>T (G412G), 2677G>T (A893S) and 3435C>T (I1145I). The frequency of the synonymous 3435C>T polymorphism has been shown to vary significantly according to ethnicity. Existing literature suggests that the haplotype plays a role in response to drugs and disease susceptibility. This review summarizes recent findings on the 3435C>T polymorphism of MDR1 and the haplotype to which it belongs. A possible molecular mechanism of action by ribosome stalling that can change protein structure and function by altering protein folding is discussed.|ATP Binding Cassette Transporter, Subfamily B[MESH]|ATP Binding Cassette Transporter, Subfamily B, Member 1/*genetics/physiology[MESH]|Amino Acid Sequence[MESH]|Animals[MESH]|Base Sequence[MESH]|Cell Line[MESH]|Ethnicity/genetics[MESH]|Haplotypes[MESH]|Humans[MESH]|Mice[MESH]|Pharmacokinetics[MESH]|Polymorphism, Single Nucleotide[MESH]|Ribosomes/drug effects/physiology[MESH]|Substrate Specificity[MESH] |
