DISRUPTION OF THE MURINE MRP (MULTIDRUG-RESISTANCE PROTEIN) GENE LEADS TO INCREASED SENSITIVITY TO ETOPOSIDE (VP-16) AND INCREASED LEVELS OF GLUTATHIONE

The mip (multidrug resistance protein) gene has been associated with t he multidrug resistance of cancer cells irt vitro and in vivo. To gain information on its physiological role, embryonic stem cells were used to generate mice homozygous for a disruption of the mrp gene, resulti ng in complete abrogation of mrp expression. No physiological abnormal ities were observed, at least up to 4 months of age, Viability, fertil ity, and a range of histological, hematological, and serum-chemical pa rameters were similar in mrp(+/+) and mrp(-/-) mice, mrp(-/-) mice dis played an increased sensitivity to etoposide phosphate (2-fold) accomp anied by greater bone marrow toxicity,, whereas the acute toxicity of sodium arsenite was equivalent in mrp(+/+) and mrp(-/-) mice. Tissue l evels of glutathione (GSH) mere elevated in breast, lung, heart, kidne y, muscle, colon, testes, bone marrow cells, blood mononuclear leukocy tes, and blood erythrocytes of mrp(-/-) mice and were unchanged in org ans known to express little if any mrp, such as the liver and small in testine, The increase in GSH was not due to an increase in the activit y of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for G SH synthesis, The findings demonstrate that mrp is dispensable for dev elopment and growth but exerts a role in drug detoxification and GSH m etabolism.