MDR1 (ABCB1) polymorphisms: functional effects and clinical implications.

MDR1 gene encodes for P glycoprotein (P-gp), which plays an important role in bioavailability and cell-toxicity limitation of a wide range of drugs and xenobiotics. Three single nucleotide polymorphisms (SNPs) in the coding region (C3435T, C1236T and G2677T/A) are the most widely studied SNPs in MDR1 and have been related to substrate and inhibitor-dependent functional modifications in in vitro studies and reduced expression in tissues. The three SNPs exhibit the highest frequencies in Asian and Caucasians populations and the lowest in African populations. In regard to the clinical implications of MDR1 SNPs, it was found in large meta-analysis that C3435T SNP was associated with a slight increase in the susceptibility to ulcerative colitis and cancer and was related with slight modifications in tacrolimus pharmacokinetics and platinum-based chemotherapy response in lung cancer. On the other hand, C3435T SNP has shown controversial results in many other cases of disease susceptibility and drug pharmacokinetics where no meta-analyses have been performed. There is less information about C1236T and G2677T/A SNPs, which, although investigated in some diseases and drug pharmacokinetics, have a very limited number of published meta-analyses. Further studies should include analysis of the haplotype 1236T-2677T/A-3435T as well as other SNPs in MDR1, other transporters and drug metabolizers that may be related with the outcome variable.