HOMOLOGS OF THE HUMAN MULTIDRUG-RESISTANCE GENES MRP AND MDR CONTRIBUTE TO HEAVY-METAL RESISTANCE IN THE SOIL NEMATODE CAENORHABDITIS-ELEGANS

Acquired resistance of mammalian cells to multiple chemotherapeutic dr ugs can result from enhanced expression of the multidrug resistance-as sociated protein (MRP), which belongs to the ABC transporter superfami ly, ABC transporters play a role in the protection of organisms agains t exogenous toxins by cellular detoxification processes, We have ident ified four MRP homologues in the soil nematode Caenorhabditis elegans, and we have studied one member, mrp-1, in detail, Using an mrp::lacZ gene fusion, mrp-1 expression was found in cells of the pharynx, the p harynx-intestinal valve and the anterior intestinal cells, the rectum- intestinal valve and the epithelial cells of the vulva, Targeted inact ivation of mrp-1 resulted in increased sensitivity to the heavy metal ions cadmium and arsenite, to which wild-type worms are highly toleran t. The most pronounced effect of the mrp-1 mutation is on the ability of animals to recover from temporary exposure to high concentrations o f heavy metals, Nematodes were found to be hypersensitive to heavy met als when both the MRP homologue, mrp-1, and a member of the P-glycopro tein (Pgp) gene family, pgp-1, were deleted, We conclude that nematode s have multiple proteins, homologues of mammalian proteins involved in the cellular resistance to chemotherapeutic drugs, that protect them against heavy metals.