{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:47:47Z","timestamp":1792734467221,"version":"4.5.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,4,15]]},"abstract":"<jats:p>\n                    The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the\n                    <jats:italic>mdr1b<\/jats:italic>\n                    gene [\n                    <jats:italic>mdr1b<\/jats:italic>\n                    (\u2212\/\u2212) mice] and in both the\n                    <jats:italic>mdr1a<\/jats:italic>\n                    and\n                    <jats:italic>mdr1b<\/jats:italic>\n                    genes [\n                    <jats:italic>mdr1a\/1b<\/jats:italic>\n                    (\u2212\/\u2212) mice]. In spite of the host of functions speculatively attributed to the mdr1-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum\u2013chemical, and immunological parameters were not abnormal in\n                    <jats:italic>mdr1a\/1b<\/jats:italic>\n                    (\u2212\/\u2212) mice. The high level of mdr1b P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically,\n                    <jats:italic>mdr1a\/1b<\/jats:italic>\n                    (\u2212\/\u2212) mice behaved similarly to the previously analyzed\n                    <jats:italic>mdr1a<\/jats:italic>\n                    (\u2212\/\u2212) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of\n                    <jats:italic>mdr1a\/1b<\/jats:italic>\n                    (\u2212\/\u2212) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy.\n                    <jats:italic>mdr1a\/1b<\/jats:italic>\n                    (\u2212\/\u2212) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.8.4028","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:43:20Z","timestamp":1027680200000},"page":"4028-4033","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":764,"title":["Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting)\u2009P-glycoproteins"],"prefix":"10.1073","volume":"94","author":[{"given":"Alfred H.","family":"Schinkel","sequence":"first","affiliation":[{"name":"Divisions of Molecular Biology, Molecular Genetics, Immunology, and Clinical Chemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and Department of Hematology, University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Mayer","sequence":"additional","affiliation":[{"name":"Divisions of Molecular Biology, Molecular Genetics, Immunology, and Clinical Chemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and Department of Hematology, University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"Wagenaar","sequence":"additional","affiliation":[{"name":"Divisions of Molecular Biology, Molecular Genetics, Immunology, and Clinical Chemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and Department of Hematology, University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla A. 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