Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.
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.
Schinkel
A H
AH
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
Mayer
U
U
Wagenaar
E
E
Mol
C A
CA
van Deemter
L
L
Smit
J J
JJ
van der Valk
M A
MA
Voordouw
A C
AC
Spits
H
H
van Tellingen
O
O
Zijlmans
J M
JM
Fibbe
W E
WE
Borst
P
P
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D004077:Digoxin