Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment...

There is a subpopulation of the CF-1 mouse strain that is very sensitive to the neurotoxicity induced by the avermectins, a class of natural products widely used in veterinary and human medicine as anti-parasitic agents. This sensitivity results from a lack of P-glycoprotein in the intestine and brain of sensitive animals, allowing increased penetration of these compounds in the blood and brain, respectively. We describe a restriction fragment length polymorphism that is able to predict which animals will be deficient in this protein, confirming at the genetic level a heterogeneous population of this mouse strain. Breeding studies demonstrated that the inheritance of the markers follows a normal Mendelian autosomal pattern. Sensitive "-/-" animals are deficient in P-glycoprotein in those tissues known to express primarily mdr1a, but have normal P-glycoprotein levels in tissues known to express primarily mdr1b or mdr2, suggesting that the defect in the sensitive animals is limited to the mdr1a gene. The P-glycoprotein expression in the brain is dependent on the genotype, which also determines the susceptibility to the avermectin-induced neurotoxicity, with the "-/-" animals being most sensitive, and the "+/-" animals having less P-glycoprotein and therefore increased CNS sensitivity compared to the "+/+" animals. The ability to segregate this strain into -/- and +/+ animals may prove useful for examining the physiological role of P-glycoprotein in drug absorption and distribution and related toxicity. These data also provide a warning that experiments carried out with P-glycoprotein substrates in the heterogeneous population of the CF-1 mouse must be interpreted with caution.