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 mdr1-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 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, 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.

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…To determine whether expression of ABC-like genes was needed for the SP phenotype, mice with targeted disruptions of the mdr1a/mdr1b genes were analyzed, and no difference in the number of SP cells relative to wildtype mice was observed, demonstrating that ABCB1 is not required for the SP phenotype. In the same study, it was found that cells transfected with a ABCG2 cDNA readily expelled Hoechst dye but not Rho123, and that efflux activity was abolished by reserpine (an inhibitor of multidrug transporters [161]), and these findings are consistent with the Hoechst-low, Rho-bright phenotype of bone-marrow SP cells from ABCB1-negative mice [162,163]. However, studies by Zhou et al [147,155,164] have demonstrated that loss of ABCG2 gene expression leads to a significant reduction in the number of SP cells in the bone marrow and that ABCG2 expression is necessary for the SP phenotype in HSCs and they hypothesized that ABCG2 defines the SP stem cell phenotype and it provides protection from cytotoxic substrates.…”

“…Taken together, these results indicate a link between ABCG2 expression and the SP phenotype. Apart from that, the intensity of ABCG2 expression increased distally from the non-SP cells towards the SP cells, leading to the conclusion that the expression of ABCG2 transporter can directly confer the SP phenotype in transduced primary bone-marrow cells both in vitro and in vivo [162][163][164][165]. Finally, the same authors also found that the ABCG2 transporter was expressed in a highly regulated manner, with the highest expression in primitive cells and subsequent downregulation following commitment to differentiation.…”

Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption

“…The first-mentioned assumption is supported by the findings that after subcutaneous injection of AMI, the plasma concentrations of AMI and its metabolites did not differ between mdr1ab Ϫ/Ϫ mice and FVB control mice (data not shown). A reduced elimination of a number of intravenously administered substrates of P-glycoprotein has been observed in P-glycoprotein Ϫ/Ϫ mutants (Mayer et al 1996;Borst and Schinkel 1997;Schinkel et al 1997;Sparreboom et al 1997).…”

P-glycoprotein (encoded by multidrug resistance genes) is not required for interleukin-2 secretion in mice and humans

“…These mice are viable and appear phenotypically normal; however, they show an increased sensitivity to the centrally neurotoxic pesticide and chemotherapeutic agents and demonstrate that P-gp is a major P-glycoprotein in the blood-brain barrier. 40 In the immune system, we proposed that P-gp might play a role in the transport of cytokines and growth factors. 26 Young and Krasney 41 examined a role of P-gp in the secretion of IL-1␤ (that lacks signal sequence; therefore, its mechanism of secretion is unknown).…”