Drug resistance caused by multidrug resistance-associated proteins.

Three types of drug efflux pumps, the multidrug resistance gene 1 (MDR1 or ABCB1)-encoded P glycoprotein, the multidrug resistance-associated protein (MRP or ABCC1) and breast cancer resistance protein (BCRP or ABCG2) may play an important part in the intrinsic or acquired defence of cells against drugs. Recent studies have begun to show the broad tissue distribution and drug substrate specificity of the seven MRP family members (MRP1-7; or ABCC1-6 and ABCC10). MRPs are (multispecific) organic anion transporters, which can transport negatively charged anionic drugs and neutral drugs conjugated to glutathione, glucuronate or sulfate. MRP4 and MRP5 broaden the spectrum of drug resistance to nucleotide analogue drugs. Some MRPs can also transport neutral drugs if co-transported with glutathione. MRP1 and MRP5 are abundant in almost every organ and are prominently present in the brain. High levels of MRP1 are present in the epithelium of the choroid plexus. Using mutant mice lacking a functional Mrp1 gene, we have previously shown the contribution of MRP1 to the blood-CSF (cerebrospinal fluid) drug permeability barrier. Recent studies indicate that the very low levels of MRP1 or MDR1 present in fibroblasts affect their sensitivity to a wide range of clinically important cytotoxic drugs. Even low concentrations of drug transporters may therefore protect cells against drugs.