Dzierlenga Anika L, Clarke John D, Klein David M, Anumol Tarun, Snyder Shane A, Li HongYu, Cherrington Nathan J
Department of Pharmacology and Toxicology (A.L.D., J.D.C., D.M.K., H.Y.L., N.J.C.); Department of Chemical and Environmental Engineering (T.A., S.A.S.), University of Arizona, Tucson, Arizona.
Department of Pharmacology and Toxicology (A.L.D., J.D.C., D.M.K., H.Y.L., N.J.C.); Department of Chemical and Environmental Engineering (T.A., S.A.S.), University of Arizona, Tucson, Arizona
J Pharmacol Exp Ther. 2016 Aug;358(2):246-53. doi: 10.1124/jpet.116.234310. Epub 2016 May 27.
Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed.
肝脏多药耐药相关蛋白2（MRP2）为许多外源性物质提供胆汁排泄途径。该途径的破坏会导致这些化合物的潴留，并最终可能引发药物不良反应。在非酒精性脂肪性肝炎（NASH）（非酒精性脂肪肝病的晚期阶段，其特征为脂肪堆积、氧化应激、炎症和纤维化）中，已观察到MRP2从胆小管膜上错位。在人类NASH以及啮齿动物蛋氨酸和胆碱缺乏（MCD）饮食模型中均观察到了MRP2/Mrp2错位，但尚不清楚其对MRP2整体转运能力的影响程度。培美曲塞是一种用于非小细胞肺癌的抗叶酸化疗药物，但其肝胆排泄途径尚未明确。本研究的目的是使用一种专一性的Mrp2转运底物来量化NASH中Mrp2功能的丧失。为了确定培美曲塞是否为专一性的Mrp2底物，比较了野生型和Mrp2（-/-）大鼠之间培美曲塞的累积胆汁排泄情况。在Mrp2（-/-）大鼠的胆汁中未检测到培美曲塞，这表明培美曲塞的胆汁排泄完全依赖于Mrp2的功能。比较MCD组和对照组动物之间培美曲塞的胆汁排泄情况，发现NASH中胆汁排泄的转运体依赖性降低了60%。本研究确定Mrp2是培美曲塞唯一的胆汁排泄机制，使其成为一种用于研究Mrp2功能的有用的体内探针底物，并量化了NASH中功能的丧失。这一机制特点可能为深入了解NASH对培美曲塞个体间反应差异的影响提供有用的见解。
