Effect of a Common Genetic Variant (p.V444A) in the Bile Salt Export Pump on the Inhibition of Bile Acid Transport by Cholestatic Medications.

The bile salt export pump (BSEP) is the primary canalicular transporter responsible for the secretion of bile acids from hepatocytes into bile canaliculi, and inhibition of this transporter has been associated with drug-induced liver injury (DILI). A common variant (rs2287622; p.V444A) in the gene encoding for BSEP has been associated with increased risk of cholestatic DILI. Although 444V BSEP (reference) and 444A BSEP (variant) do not differ in the transport kinetics of TCA, transport of the more abundant GCA has not been investigated. Importantly, differences in susceptibility of 444V and 444A BSEP to inhibition by drugs causing cholestatic DILI has not been investigated. To address these issues, the transport kinetics of GCA were evaluated by incubating membrane vesicles expressing either 444V or 444A BSEP with GCA over a range of concentrations (1, 10, 25, 50, 100 µM). The ability of commonly used cholestatic medications to inhibit transport of TCA and GCA by the reference and variant proteins were compared. Resulting data indicated that GCA transport kinetics for reference and variant BSEP followed Michaelis-Menten kinetics and were not statistically different (Vmax: 1132 ± 246 vs. 959 ± 256 pmol/min/mg protein, respectively; Km: 32.7 ± 18.2 vs. 45.7 ± 25.5 µM, respectively). There were no statistically significant differences between the reference and variant BSEP in the inhibition of TCA or GCA transport by the cholestatic drugs tested. In conclusion, an association between the variant BSEP and risk for cholestatic DILI due to the drugs tested cannot be accounted for by differential inhibition of TCA or GCA transport.