Disruption of the Murine MRP (Multidrug Resistance Protein) Gene Leads to Increased Sensitivity to Etoposide (VP-16) and Increased Levels of Glutathione1

The imp (multidrug resistance protein) gene has been associated with the multidrug resistance of cancer cells in 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, resulting in complete abrogation of imp expression. No physiological abnormalities were observed, at least up to 4 months of age. Viability, fertility, and a range of histological, hematological, and serum-chemical parameters were similar in mrp(+I+) and mrp(—/--)mice. mrp(—I—) mice displayed an increased sensitivity to etoposide phosphate (2-fold) accompanied by greater bone marrow toxicity, whereas the acute toxicity of sodium ar senite was equivalent in mrp(+/+) and mrp(—/—) mice. Tissue levels of glutathione (GSH) were elevated in breast, lung, heart, kidney, muscle, colon,testes,bonemarrowcells,bloodmononuclearleukocytes, andblood erythrocytes ofmrp(-I--) mice and were unchanged organs known to express little if any mrp, such as the liver and small intestine. The increase in GSH was not due to an increase In the activity of -y-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis. The findings demonstrate that m,p is dispensable for development and growth but exerts a role in drug detoxification and GSH metabolism.