A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function

Abstract

The 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.

MDR1 C3435T polymorphism in Mexican patients with breast cancer

“…Future studies should consider interethnic variations as well as protein interactions in order to provide more conclusive information about the role of the MDR1 C3435T polymorphism in the course and outcome of breast cancer. Although this polymorphism by itself is not causative, there are nearly 50 other SNPs in the MDR1 gene, including 30 that lead to amino acid substitutions (Fung and Gottesman, 2009). Moreover, other genes may also be implicated in the etiology of sporadic breast cancer.…”

“…The multi-drug resistance 1 (MDR1) gene is a member of the ABC family and encodes a membrane-bound phosphoglycoprotein (P-gp), which acts as an efflux pump and provides cell protection against various substances such as organic cations, carbohydrates, amino acids, some antibiotics, polysaccharides, and proteins (Hoffmeyer, 2000;Marzolini et al, 2004;Ieiri, 2012). Accordingly, P-gp is highly expressed in the kidney, adrenal gland, liver, blood-brain barrier, placenta, and testis (Fojo et al, 1987;Sugawara et al, 1989;Fung and Gottesman, 2009). In each tissue, P-gp directly influences drug efficacy, and in cancer cells, its expression determines the degree of chemotherapy resistance.…”

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

“…Various mechanisms are involved in the MDR of cancer, including the induction of the anti-apoptotic machinery, an increase in intracellular drug efflux and a reduction in drug uptake (3). Overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, are one of most common reasons for the development of MDR in cancer cells (4)(5)(6)(7).…”

MDR1 gene polymorphisms and P-glycoprotein expression in respiratory diseases

“…The two halves are separated by a flexible linker region, and the two ATP-binding domains are structurally similar. All 12 trans-membrane domains are found in the plasma membrane 8 . P-gp is expressed in the apical membrane of cells with excretory functions, such as those in the liver, kidney, small intestine, stomach, and the blood-brain barrier 9,10 .…”