Hepatobiliary transporters and bile secretion machinery

The hepatobiliary transporters and bile secretion machinery consist of a coordinated network of membrane proteins that facilitate the movement of bile acids, bilirubin, and xenobiotics from the blood into the bile (Pauli-Magnus et al., 2006). This system includes basolateral uptake transporters, such as the Na+/taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptides (OATPs), as well as canalicular efflux transporters like the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) (NIH, 2024). These proteins are essential for maintaining bile acid homeostasis, aiding in the digestion of dietary fats, and providing a major route for the excretion of metabolic waste and drugs (MDPI, 2024). Dysfunction of this machinery, whether due to genetic mutations or drug-induced inhibition, can lead to the accumulation of toxic bile acids within the liver, resulting in cholestasis and severe liver injury (Semanticscholar, 2009). Therapeutic agents like obeticholic acid and odevixibat target components of this machinery to treat cholestatic conditions by either promoting bile flow or reducing bile acid reabsorption (MDPI, 2024). Conversely, many drugs are screened for their potential to inhibit these transporters, particularly BSEP, to avoid drug-induced liver injury (DILI) during development (NIH, 2024). The machinery also plays a role in the pharmacokinetics of various drugs, determining their biliary clearance and potential for enterohepatic circulation (Semanticscholar, 2009). Overall, this complex system is a vital physiological apparatus and a significant target for both drug efficacy and safety evaluations.

Other names

Hepatobiliary transport systemBile acid transport machineryBiliary excretion systemHepatocellular transport system

Drugs modulate the hepatobiliary machinery by acting as substrates, inhibitors, or inducers of specific transporters such as BSEP, NTCP, and MRP2, or by activating nuclear receptors like FXR that regulate the transcription of these transporter genes (Pauli-Magnus et al., 2006; NIH, 2024).