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[Cancer Research 57, 5238-5242, December 1, 1997]
© 1997 American Association for Cancer Research
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Disruption of the Murine MRP (Multidrug Resistance Protein) Gene Leads to Increased Sensitivity to Etoposide (VP-16) and Increased Levels of Glutathione1

Aurelio Lorico, Germana Rappa, Rick A. Finch, Di Yang, Richard A. Flavell and Alan C. Sartorelli2

Department of Pharmacology, [A. L., G. R., R. A. Fi., A. C. S.], Howard Hughes Medical Institute, Section of Immunobiology [D. Y., R. A. Fl.] and Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

The mrp (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 mrp 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(+/+) and mrp(-/-) mice. mrp(-/-) mice displayed an increased sensitivity to etoposide phosphate (2-fold) accompanied by greater bone marrow toxicity, whereas the acute toxicity of sodium arsenite was equivalent in mrp(+/+) and mrp(-/-) mice. Tissue levels of glutathione (GSH) were elevated in breast, lung, heart, kidney, muscle, colon, testes, bone marrow cells, blood mononuclear leukocytes, and blood erythrocytes of mrp(-/-) mice and were unchanged in 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 {gamma}-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis. The findings demonstrate that mrp is dispensable for development and growth but exerts a role in drug detoxification and GSH metabolism.

1 Presented in part at the 88th Annual Meeting of the American Association for Cancer Research, April 12–16, 1997, San Diego, California. This work was supported by USPHS Grants CA-66739 and CA-16359 from the National Cancer Institute.

2 To whom requests for reprints should be addressed, at the Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.

Received 8/21/97. Accepted 10/17/97.




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