Genetic variations in drug metabolizing enzymes and targets are established 
determinants of adverse drug reactions and interactions, but less is known about 
the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) 
is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the 
ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related 
ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a 
distinctive pattern of tissue expression and substrate specificity. Together, 
these five transporters play important roles in the disposition and elimination 
of drugs and other organic anions, and in maintenance of blood-tissue barriers, 
as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, 
Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, 
corresponding to a human condition known as Dubin-Johnson syndrome (DJS). 
Naturally occurring mutations in MRP/ABCC-related drug transporters have been 
reported, some of which are non-synonymous single nucleotide polymorphisms. The 
consequences of the resulting amino acid changes can sometimes be predicted from 
in vitro site-directed mutagenesis studies or from knowledge of mutations of 
analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma 
elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic 
hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of 
sequence variants and haplotype analysis, together with in vitro biochemical 
validation assays and pharmacological studies in knockout animals, should make 
it possible to determine how genetic variation in the MRP-related transporters 
contributes to the range of responses to drugs and chemicals observed in 
different human populations.