Hepatitis C Virus-related Cirrhosis is a Major Determinant of the Expression Levels of Hepatic Drug Transporters

Abstract

Hepatic drug transporters are responsible for both hepatic uptake and the biliary excretion of drugs. Expression changes in hepatic drug transporter genes have been observed in various pathophysiological conditions. However, it has not been comprehensively investigated what factors substantially influence the mRNA levels of hepatic drug transporters. In this study, we quantified the mRNA expression of 17 drug transporters using noncancerous liver tissue samples and carried out stepwise multiple regression analysis to identify the factors affecting their expression from 18 clinical variables. For 17 drug transporters, the mRNA level of organic anion transporting polypeptide (OATP) 2B1 was highest, followed by that of organic cation transporter 1, organic anion transporter 2, OATP1B1, OATP1B3, multidrug resistance-associated protein (MRP) 6, and MRP3. Stepwise multiple regression analysis demonstrated MRP4 mRNA level to be predicted with the greatest accuracy among 17 drug transporters. Of clinical variables entered into the prediction model for MRP4, hepatitis C virus (HCV) infection and liver cirrhosis were crucial factors affecting MRP4 mRNA and protein levels. Furthermore, HCV-related cirrhosis influenced the mRNA levels of 8 drug transporters besides MRP4. These findings indicate that HCV-related cirrhosis is a crucial factor affecting the expression of hepatic drug transporters, especially MRP4.