Received for publication February 13, 2007.
Revised July 12, 2007.
Accepted for publication July 16, 2007.

Efflux Transporter Expression and Acetaminophen Metabolite Excretion are Altered in Rodent Models of Non-Alcoholic Fatty Liver Disease

Abstract

Efflux transporters are responsible for the excretion of numerous xenobiotics and endobiotics and thus play an essential role in proper liver and kidney function. Non-alcoholic fatty liver diseases (NAFLD) comprise a spectrum of disorders that range from simple fatty liver (SFL) to non-alcoholic steatohepatitis (NASH). While the precise events leading to NAFLD are unclear, even less is known about the effects on efflux transporter expression and drug disposition. The purpose of this study was to determine the effect of NAFLD on efflux transporter expression in rat liver, as well as acetaminophen (APAP) metabolite excretion. To simulate SFL and NASH, rats were fed either a high-fat (HF) or a methionine-, choline-deficient (MCD) diet for 8 weeks. In the livers of MCD rats, there were striking increases in both mRNA and protein levels of Mrp3, Mrp4 and Bcrp, as well as increased Mrp2 protein. Following administration of a non-toxic dose of APAP, biliary concentrations of APAP-sulfate, APAP-glucuronide (APAP-GLUC) and APAP-glutathione were reduced in MCD rats. The effects of the HF diet on both transporter expression and APAP disposition were by comparison far less dramatic than the MCD diet-induced alterations. While APAP-sulfate levels were also decreased in MCD rat plasma, the levels of the Mrp3 substrate APAP-GLUC were elevated. Urinary elimination of APAP metabolites was identical between groups, except for APAP-GLUC, the concentration of which was 80% higher in MCD rats. These studies correlate increased hepatic Mrp3 protein in the MCD model of NASH with increased urinary elimination of APAP-GLUC. Furthermore, the proportional shift in elimination of APAP metabolites from bile to urine indicates that MCD-induced alterations in efflux transporter expression can affect the route of drug elimination.

Key words: biliary excretion, gene regulation, hepatic elimination, hepatic transport, hepatobiliary disposition, hepatobiliary transport, liver disease, MRP, pharmacokinetics, transporters

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