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. Nonalcoholic fatty liver diseases (NAFLDs) comprise a spectrum of disorders that range from simple fatty liver (SFL) to nonalcoholic steatohepatitis (NASH). Although 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 on acetaminophen (APAP) metabolite excretion. To simulate SFL and NASH, rats were fed either a high-fat (HF) or a methionine- and choline-deficient (MCD) diet for 8 weeks. In the livers of MCD rats, there were striking increases in both mRNA and protein levels of multidrug resistance-associated protein (Mrp) 3, Mrp4, and breast cancer resistance protein, as well as increased Mrp2 protein. After administration of a nontoxic 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. Whereas 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.
Footnotes
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This work was supported by National Institutes of Health Grants DK068039, ES06694, and ES007091.
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doi:10.1124/dmd.107.015107.
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ABBREVIATIONS: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; SFL, simple fatty liver; HF, high-fat; MCD, methionine- and choline-deficient; Mrp, multidrug resistance-associated protein; Bsep, bile salt excretory protein; Bcrp, breast cancer resistance protein; APAP, acetaminophen; APAP-SULF acetaminophen-sulfate; APAP-GLUC, acetaminophen-glucuronide; GSH, glutathione; APAP-GSH, acetaminophen-glutathione; HPLC, high-performance liquid chromatography; H&E, hematoxylin and eosin; APAP-CG/CYS, acetaminophen-cysteinylglycine/cysteine; APAP-NAC, acetaminophen-mercapturate (N-acetyl-l-cysteine); TNF-α. tumor necrosis factor-α; IL, interleukin.
- Received February 6, 2007.
- Accepted July 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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