Lickteig Andrew J, Fisher Craig D, Augustine Lisa M, Aleksunes Lauren M, Besselsen David G, Slitt Angela L, Manautou Jose E, Cherrington Nathan J
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Drug Metab Dispos. 2007 Oct;35(10):1970-8. doi: 10.1124/dmd.107.015107. Epub 2007 Jul 19.
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.
外排转运体负责多种外源性和内源性物质的排泄，因此在肝脏和肾脏的正常功能中发挥着重要作用。非酒精性脂肪性肝病（NAFLD）包括一系列疾病，从单纯性脂肪肝（SFL）到非酒精性脂肪性肝炎（NASH）。尽管导致NAFLD的确切机制尚不清楚，但对于其对外排转运体表达和药物处置的影响了解更少。本研究的目的是确定NAFLD对大鼠肝脏外排转运体表达以及对乙酰氨基酚（APAP）代谢产物排泄的影响。为了模拟SFL和NASH，将大鼠分别喂食高脂（HF）或蛋氨酸和胆碱缺乏（MCD）饮食8周。在MCD大鼠的肝脏中，多药耐药相关蛋白（Mrp）3、Mrp4和乳腺癌耐药蛋白的mRNA和蛋白水平均显著增加，同时Mrp2蛋白也增加。给予无毒剂量的APAP后，MCD大鼠胆汁中APAP-硫酸盐、APAP-葡萄糖醛酸苷（APAP-GLUC）和APAP-谷胱甘肽的浓度降低。相比之下，HF饮食对转运体表达和APAP处置的影响远不如MCD饮食诱导的改变显著。虽然MCD大鼠血浆中APAP-硫酸盐水平也降低，但Mrp3底物APAP-GLUC的水平升高。除APAP-GLUC外，各组间APAP代谢产物的尿排泄情况相同，MCD大鼠中APAP-GLUC的浓度高出80%。这些研究将NASH的MCD模型中肝脏Mrp3蛋白增加与APAP-GLUC尿排泄增加联系起来。此外，APAP代谢产物从胆汁到尿液排泄的比例变化表明，MCD诱导的外排转运体表达改变可影响药物的排泄途径。
