The liver is the primary organ responsible for the sinusoidal uptake, intracellular metabolism, and biliary efflux of endogenous and exogenous toxic substrates. Multidrug resistance-associated protein 2 (MRP2) is an ATP-binding dependent efflux pump mediating the biliary transport of a wide variety of endogenous and xenobiotic compounds and therefore play a critical role in physiological transport processes, drug transport and detoxification. MRP2 is mainly expressed at a highly variable level in the canalicular membrane of hepatocytes. The reasons underlying the pronounced interindividual variability in the hepatic MRP2 expression in humans are incompletely understood, but may include non-genetic factors and genetic polymorphisms of the encoding gene MRP2. Therfore, the first goal of this project is to investigate the extent of interindividual variability in the mRNA and protein expression of MRP2 in normal human liver tissue and look for correlations between individual expression levels with patients’ demographic data, laboratory parameters, underlying liver disease, and SNPs/haplotypes in the MRP2 gene. Today, many sequence variants in the MRP2 gene have been identified, but only several of them are functional characterized. For example, nonsynonymous variations in MRP2 can influence substrate-dependent changes in transporter function as well as expression by altering protein stability or subcellular localization and membrane trafficking. Our second goal is a comprehensive analysis of the impact of natural protein variants on the MRP2 expression and function with the overall goal of identification of variants affecting drug disposition.