Abstract
Suspected ivermectin hypersensitivity has been reported in the Eurasian bullfinch and some related passerine birds. However, the underlying cause and pharmacological mechanism have not been systematically investigated. In mammals, ivermectin hypersensitivity in dogs and cats has been linked to mutations in the ABCB1 gene, which encodes the P-glycoprotein drug efflux transporter. In the present study, the full-length ABCB1 transcript of the Eurasian bullfinch (Pyrrhula pyrrhula) was amplified and cloned. Sequence analysis identified a tandem-repeat insertion consisting of two identical 10-amino acid motifs within the ABCB1 linker region, a feature absent from human and chicken ABCB1. A systematic analysis of this insertion motif across available ABCB1 sequences from passerine birds identified four distinct variants: a single-motif insertion, a tandem repeat insertion, a triple repeat insertion, or complete absence of the insertion. These variants showed a predominant, though not exclusive, association with specific Passeriformes families. Heterologous expression of Eurasian bullfinch ABCB1 in HEK293 cells revealed significantly reduced total protein levels of the wild-type ABCB1 transporter compared with a mutant lacking the tandem repeat insertion. However, efflux activity toward the fluorescent ABCB1 substrate Rhodamine 123 did not differ between the wild-type and mutant transporters. Likewise, inhibition of Rhodamine 123 efflux by the established ABCB1 inhibitors ivermectin and tariquidar was comparable between the Eurasian bullfinch ABCB1 variants and with canine ABCB1. In conclusion, although a distinct genetic feature was identified in the ABCB1 linker region of some passerine birds, no functional differences in Rhodamine 123 efflux or inhibitor sensitivity were detected. Our in vitro data do not support a role of this ABCB1 insertion for the suspected ivermectin hypersensitivity in the Eurasian bullfinch.