title: Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.
abstract: 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 mdr1b gene [mdr1b (-/-) mice] and in both the mdr1a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of functions speculatively attributed to the mdrl-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunological parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdrlb 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, mdr1a/1b (-/-) mice behaved similarly to the previously analyzed mdr1a (-/-) 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 mdr1a/1b (-/-) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) 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.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: U
authors.initials: U
authors.lastname: Mayer
authors.forename: E
authors.initials: E
authors.lastname: Wagenaar
authors.forename: C A
authors.initials: CA
authors.lastname: Mol
authors.forename: L
authors.initials: L
authors.lastname: van Deemter
authors.forename: J J
authors.initials: JJ
authors.lastname: Smit
authors.forename: M A
authors.initials: MA
authors.lastname: van der Valk
authors.forename: A C
authors.initials: AC
authors.lastname: Voordouw
authors.forename: H
authors.initials: H
authors.lastname: Spits
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: J M
authors.initials: JM
authors.lastname: Zijlmans
authors.forename: W E
authors.initials: WE
authors.lastname: Fibbe
authors.forename: P
authors.initials: P
authors.lastname: Borst
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D051379:Mice; D018345:Mice, Knockout / Q000196:embryology / Q000502:physiology*; D011247:Pregnancy
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D004077:Digoxin