ABCB4 is almost exclusively expressed in the liver, where it plays an essential role
in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms
and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders,
attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may
lead to cholestasis and drug-induced liver injury (DILI), although compared with other
drug transporters, there are only a few identified substrates and inhibitors of ABCB4.
Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence
with ABCB1, also known to have common drug substrates and inhibitors, we aimed to
develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport
assays. This in vitro system allows the screening of ABCB4-specific drug substrates
and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute
a reproducible, conclusive, and easy to use assay to study drug interactions with
digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved
that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent
with prior findings concerning hepatotoxicity causality and provide new insights for
identifying drugs as potential ABCB4 inhibitors and substrates.
