INVESTIGATING THE ROLE OF OCT1 TRANSPORTER IN DRUG UPTAKE

Abstract

ABSTRACT The human organic cation transporter (OCT1) is a key transporter that is mainly expressed in the liver. It is one of the transmembrane transporters that is highly expressed at the sinusoidal side of the hepatocytes and plays a role in the clearance of various organic cations from the blood. OCT1 functions as an uptake transporter for nutrients such as vitamin B1, neurotransmitters (e.g. serotonin), and various therapeutic and chemotherapeutic drugs. Anti-cancer drugs such as sorafenib were the most studied substrates. Some studies suggested that OCT1 expression is associated with the response to sorafenib in hepatocellular carcinoma patients. Others reported that the activity of sorafenib does not rely on OCT1. In this thesis, we could not conclude whether the response to sorafenib is associated with OCT1 expression, but invoke the possibility that the related transporter OCT2 could be involved in sorafenib uptake. Despite OCT1 broad substrate specificities, no specific high-affinity substrate has been identified for this transporter. As such, we used docking studies and analyzed several molecules for their potential to be transported by OCT1. Our analysis revealed menadione as a likely substrate, which is a precursor for vitamin K. In this thesis, we indirectly assessed the transport of menadione as a possible substrate for OCT1 by comparing the sensitivity of HeLa wild-type cells and HeLa deleted for OCT1 using clonogenic assays. The preliminary results showed that OCT1 might be implicated in the transport of menadione. However, more studies are needed to confirm these preliminary findings, as well as using a relevant liver cell line such as HepG2.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences